Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by more than 10% (PVS1_S). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:25434006, PS3_S). The variant has been reported to be associated with MFAP5 related disorder (ClinVar ID: VCV000162199, PMID:25434006).Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
ClinVar Genomic variation as it relates to human health
NM_003480.4(MFAP5):c.472C>T (p.Arg158Ter)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(7)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Conflicting classifications of pathogenicity
Pathogenic(3); Likely pathogenic(2); Uncertain significance(1)
Pathogenic(3); Likely pathogenic(2); Uncertain significance(1)
7
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_003480.4(MFAP5):c.472C>T (p.Arg158Ter)
Variation ID: 162199 Accession: VCV000162199.26
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 12p13.31 12: 8648141 (GRCh38) [ NCBI UCSC ] 12: 8800737 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jan 11, 2015 Jul 23, 2024 Jul 17, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_003480.4:c.472C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003471.1:p.Arg158Ter nonsense NM_001297709.2:c.442C>T NP_001284638.1:p.Arg148Ter nonsense NM_001297710.2:c.406C>T NP_001284639.1:p.Arg136Ter nonsense NM_001297711.2:c.397C>T NP_001284640.1:p.Arg133Ter nonsense NM_001297712.2:c.280C>T NP_001284641.1:p.Arg94Ter nonsense NR_123733.2:n.743C>T non-coding transcript variant NR_123734.2:n.713C>T non-coding transcript variant NC_000012.12:g.8648141G>A NC_000012.11:g.8800737G>A NG_041814.1:g.19748C>T - Protein change
- R158*, R133*, R136*, R148*, R94*
- Other names
- -
- Canonical SPDI
- NC_000012.12:8648140:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Trans-Omics for Precision Medicine (TOPMed) 0.00000
Exome Aggregation Consortium (ExAC) 0.00004
The Genome Aggregation Database (gnomAD), exomes 0.00004
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| LOC126861443 | - | - | - | GRCh38 | - | 55 |
| MFAP5 | - | - |
GRCh38 GRCh37 |
211 | 292 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
|
Jul 17, 2023 | RCV000149579.16 | |
|
Isolated thoracic aortic aneurysm
|
Likely pathogenic (1) |
criteria provided, single submitter
|
Sep 1, 2018 | RCV001374805.9 |
| Likely pathogenic (1) |
criteria provided, single submitter
|
May 5, 2023 | RCV002516008.10 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(Sep 01, 2018)
|
criteria provided, single submitter
Method: research
|
Isolated thoracic aortic aneurysm
Affected status: yes
Allele origin:
germline
|
Department of Vascular Biology, Beijing Anzhen Hospital
Accession: SCV001439506.1
First in ClinVar: May 01, 2021 Last updated: May 01, 2021 |
Sex: mixed
|
|
|
Pathogenic
(Jan 03, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Aortic aneurysm, familial thoracic 9
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002058191.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
Comment:
Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by … (more)
Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by more than 10% (PVS1_S). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:25434006, PS3_S). The variant has been reported to be associated with MFAP5 related disorder (ClinVar ID: VCV000162199, PMID:25434006).Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Stroke disorder (present)
|
|
|
Pathogenic
(Feb 01, 2013)
|
criteria provided, single submitter
Method: clinical testing
|
Aortic aneurysm, familial thoracic 9
Affected status: yes
Allele origin:
germline
|
Arcensus
Accession: SCV002564574.1
First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022 |
|
|
|
Pathogenic
(Jul 27, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Aortic aneurysm, familial thoracic 9
Affected status: yes
Allele origin:
germline
|
MGZ Medical Genetics Center
Accession: SCV002581617.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PVS1, PS3, PM2_SUP
|
Number of individuals with the variant: 1
Sex: male
|
|
|
Likely pathogenic
(May 05, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003440434.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
Experimental studies have shown that this premature translational stop signal affects MFAP5 function (PMID: 25434006). In summary, the currently available evidence indicates that the variant … (more)
Experimental studies have shown that this premature translational stop signal affects MFAP5 function (PMID: 25434006). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 162199). This premature translational stop signal has been observed in individuals with MFAP5-related conditions (PMID: 25434006, 33824467). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs727502791, gnomAD 0.03%). This sequence change creates a premature translational stop signal (p.Arg158*) in the MFAP5 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 16 amino acid(s) of the MFAP5 protein. (less)
|
|
|
Uncertain significance
(Jul 17, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Aortic aneurysm, familial thoracic 9
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV005087004.1
First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 2024 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with aortic aneurysm, familial thoracic 9, (MIM#616166). However, this gene-disease association is not yet established (PanelApp). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (11 heterozygotes, 0 homozygotes). (SP) 0600 - Variant results in the partial truncation of an annotated signal peptide (PMID: 33824467). (I) 0705 - No comparable protein truncating variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported once as a VUS (LOVD), but multiple times as likely pathogenic or pathogenic (ClinVar). It has also been observed in at least two unrelated individuals with aortic aneurysm or dissection (PMID: 25434006, PMID: 33824467), but also once in a healthy cohort (PMID: 29618732). (SP) 0906 - Segregation evidence for this variant is inconclusive. This variant has segregated in a single family, where seven individuals were either affected or ambiguously affected. However, there was also a healthy obligate carrier, and another ambiguously affected individual who did not have the variant (PMID: 25434006). (I) 1001 - This variant has strong functional evidence supporting abnormal protein function. Functional studies on fibroblasts from affected individuals demonstrated a lack of extracellular protein otherwise observed in controls. This result was recapitulated in transfected HEK293 cells (PMID: 25434006). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
|
|
|
Pathogenic
(Dec 04, 2014)
|
no assertion criteria provided
Method: literature only
|
AORTIC ANEURYSM, FAMILIAL THORACIC 9
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000196555.1
First in ClinVar: Jan 11, 2015 Last updated: Jan 11, 2015 |
Comment on evidence:
In affected individuals from a 3-generation family segregating autosomal dominant thoracic aortic aneurysm-9 (AAT9; 616166), Barbier et al. (2014) identified heterozygosity for a c.472C-T transition … (more)
In affected individuals from a 3-generation family segregating autosomal dominant thoracic aortic aneurysm-9 (AAT9; 616166), Barbier et al. (2014) identified heterozygosity for a c.472C-T transition in exon 10 of the MFAP5 gene, resulting in an arg158-to-ter (R158X) substitution. The mutation was not found in unaffected family members. Analysis of patient fibroblasts demonstrated pure haploinsufficiency, and transfection studies confirmed that the R158X mutation abrogates protein production. (less)
|
Comment:
Comment:
Experimental studies have shown that this premature translational stop signal affects MFAP5 function (PMID: 25434006). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 162199). This premature translational stop signal has been observed in individuals with MFAP5-related conditions (PMID: 25434006, 33824467). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs727502791, gnomAD 0.03%). This sequence change creates a premature translational stop signal (p.Arg158*) in the MFAP5 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 16 amino acid(s) of the MFAP5 protein.
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with aortic aneurysm, familial thoracic 9, (MIM#616166). However, this gene-disease association is not yet established (PanelApp). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (11 heterozygotes, 0 homozygotes). (SP) 0600 - Variant results in the partial truncation of an annotated signal peptide (PMID: 33824467). (I) 0705 - No comparable protein truncating variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported once as a VUS (LOVD), but multiple times as likely pathogenic or pathogenic (ClinVar). It has also been observed in at least two unrelated individuals with aortic aneurysm or dissection (PMID: 25434006, PMID: 33824467), but also once in a healthy cohort (PMID: 29618732). (SP) 0906 - Segregation evidence for this variant is inconclusive. This variant has segregated in a single family, where seven individuals were either affected or ambiguously affected. However, there was also a healthy obligate carrier, and another ambiguously affected individual who did not have the variant (PMID: 25434006). (I) 1001 - This variant has strong functional evidence supporting abnormal protein function. Functional studies on fibroblasts from affected individuals demonstrated a lack of extracellular protein otherwise observed in controls. This result was recapitulated in transfected HEK293 cells (PMID: 25434006). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by more than 10% (PVS1_S). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:25434006, PS3_S). The variant has been reported to be associated with MFAP5 related disorder (ClinVar ID: VCV000162199, PMID:25434006).Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
Experimental studies have shown that this premature translational stop signal affects MFAP5 function (PMID: 25434006). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 162199). This premature translational stop signal has been observed in individuals with MFAP5-related conditions (PMID: 25434006, 33824467). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs727502791, gnomAD 0.03%). This sequence change creates a premature translational stop signal (p.Arg158*) in the MFAP5 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 16 amino acid(s) of the MFAP5 protein.
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with aortic aneurysm, familial thoracic 9, (MIM#616166). However, this gene-disease association is not yet established (PanelApp). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (11 heterozygotes, 0 homozygotes). (SP) 0600 - Variant results in the partial truncation of an annotated signal peptide (PMID: 33824467). (I) 0705 - No comparable protein truncating variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported once as a VUS (LOVD), but multiple times as likely pathogenic or pathogenic (ClinVar). It has also been observed in at least two unrelated individuals with aortic aneurysm or dissection (PMID: 25434006, PMID: 33824467), but also once in a healthy cohort (PMID: 29618732). (SP) 0906 - Segregation evidence for this variant is inconclusive. This variant has segregated in a single family, where seven individuals were either affected or ambiguously affected. However, there was also a healthy obligate carrier, and another ambiguously affected individual who did not have the variant (PMID: 25434006). (I) 1001 - This variant has strong functional evidence supporting abnormal protein function. Functional studies on fibroblasts from affected individuals demonstrated a lack of extracellular protein otherwise observed in controls. This result was recapitulated in transfected HEK293 cells (PMID: 25434006). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Evaluating the monogenic contribution and genotype-phenotype correlation in patients with isolated thoracic aortic aneurysm. | Li Y | European journal of human genetics : EJHG | 2021 | PMID: 33824467 |
| KoVariome: Korean National Standard Reference Variome database of whole genomes with comprehensive SNV, indel, CNV, and SV analyses. | Kim J | Scientific reports | 2018 | PMID: 29618732 |
| MFAP5 loss-of-function mutations underscore the involvement of matrix alteration in the pathogenesis of familial thoracic aortic aneurysms and dissections. | Barbier M | American journal of human genetics | 2014 | PMID: 25434006 |
Text-mined citations for rs727502791 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 25, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.