This variant is interpreted as a Likely pathogenic for Macrocephaly, acquired, with impaired intellectual development, autosomal dominant. The following ACMG Tag(s) were applied: PM2, PVS1.
ClinVar Genomic variation as it relates to human health
NM_001190737.2(NFIB):c.265C>T (p.Arg89Ter)
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.
Pathogenic/Likely pathogenic
7
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001190737.2(NFIB):c.265C>T (p.Arg89Ter)
Variation ID: 424344 Accession: VCV000424344.6
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 9p22.3 9: 14307286 (GRCh38) [ NCBI UCSC ] 9: 14307285 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Apr 29, 2017 Nov 3, 2024 Mar 14, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001190737.2:c.265C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001177666.1:p.Arg89Ter nonsense NM_001190738.2:c.343C>T NP_001177667.1:p.Arg115Ter nonsense NM_001369458.1:c.331C>T NP_001356387.1:p.Arg111Ter nonsense NM_001369459.1:c.331C>T NP_001356388.1:p.Arg111Ter nonsense NM_001369460.1:c.253C>T NP_001356389.1:p.Arg85Ter nonsense NM_001369461.1:c.265C>T NP_001356390.1:p.Arg89Ter nonsense NM_001369462.1:c.331C>T NP_001356391.1:p.Arg111Ter nonsense NM_001369463.1:c.253C>T NP_001356392.1:p.Arg85Ter nonsense NM_001369464.1:c.265C>T NP_001356393.1:p.Arg89Ter nonsense NM_001369465.1:c.238C>T NP_001356394.1:p.Arg80Ter nonsense NM_001369466.1:c.253C>T NP_001356395.1:p.Arg85Ter nonsense NM_001369467.1:c.238C>T NP_001356396.1:p.Arg80Ter nonsense NM_001369468.1:c.331C>T NP_001356397.1:p.Arg111Ter nonsense NM_001369469.1:c.121C>T NP_001356398.1:p.Arg41Ter nonsense NM_001369470.1:c.253C>T NP_001356399.1:p.Arg85Ter nonsense NM_001369471.1:c.265C>T NP_001356400.1:p.Arg89Ter nonsense NM_001369472.1:c.253C>T NP_001356401.1:p.Arg85Ter nonsense NM_001369473.1:c.253C>T NP_001356402.1:p.Arg85Ter nonsense NM_001369474.1:c.250C>T NP_001356403.1:p.Arg84Ter nonsense NM_001369475.1:c.265C>T NP_001356404.1:p.Arg89Ter nonsense NM_001369476.1:c.238C>T NP_001356405.1:p.Arg80Ter nonsense NM_001369477.1:c.265C>T NP_001356406.1:p.Arg89Ter nonsense NM_001369478.1:c.253C>T NP_001356407.1:p.Arg85Ter nonsense NM_001369481.1:c.265C>T NP_001356410.1:p.Arg89Ter nonsense NM_005596.3:c.265C>T NP_005587.2:p.Arg89Ter nonsense NC_000009.12:g.14307286G>A NC_000009.11:g.14307285G>A - Protein change
- R89*, R115*, R41*, R80*, R84*, R111*, R85*
- Other names
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- Canonical SPDI
- NC_000009.12:14307285:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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- 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. |
|||
| NFIB | - | - |
GRCh38 GRCh37 |
132 | 259 | |
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. |
|---|---|---|---|---|
| Pathogenic (1) |
criteria provided, single submitter
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- | RCV000677901.2 | |
| Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Jul 31, 2020 | RCV000754571.7 | |
| Pathogenic (1) |
criteria provided, single submitter
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Mar 14, 2023 | RCV004771807.1 |
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. |
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|---|---|---|---|---|---|
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Pathogenic
(-)
|
criteria provided, single submitter
Method: research
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Intellectual disability
Macrocephaly (Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
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Department of Human Genetics, University Hospital Magdeburg
Accession: SCV000803744.1
First in ClinVar: Aug 26, 2018 Last updated: Aug 26, 2018 |
Sex: male
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Likely pathogenic
(Oct 02, 2019)
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criteria provided, single submitter
Method: curation
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Macrocephaly, acquired, with impaired intellectual development
Affected status: unknown
Allele origin:
unknown
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SIB Swiss Institute of Bioinformatics
Accession: SCV001146839.1
First in ClinVar: Jan 20, 2020 Last updated: Jan 20, 2020 |
Comment:
This variant is interpreted as a Likely pathogenic for Macrocephaly, acquired, with impaired intellectual development, autosomal dominant. The following ACMG Tag(s) were applied: PM2, PVS1.
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Likely pathogenic
(Jul 31, 2020)
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criteria provided, single submitter
Method: clinical testing
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MACROCEPHALY, ACQUIRED, WITH IMPAIRED INTELLECTUAL DEVELOPMENT
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001426836.1
First in ClinVar: Aug 09, 2020 Last updated: Aug 09, 2020 |
Comment:
Variant summary: NFIB c.265C>T (p.Arg89X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: NFIB c.265C>T (p.Arg89X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 251404 control chromosomes (gnomAD). c.265C>T has been reported in the literature in at least one individual affected with macrocephaly, developmental delays, and mild-moderate intellectual disability (e.g. Schanze_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=1) and likely pathogenic/pathogenic (n=3). Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Pathogenic
(Jan 30, 2020)
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criteria provided, single submitter
Method: clinical testing
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Macrocephaly, acquired, with impaired intellectual development
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Genomic Medicine Lab, University of California San Francisco
Study: CSER-P3EGS
Accession: SCV001572921.1 First in ClinVar: May 05, 2021 Last updated: May 05, 2021 |
Sex: male
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Pathogenic
(Mar 14, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000574143.4
First in ClinVar: Apr 29, 2017 Last updated: Nov 03, 2024 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32902921, 33130023, 30388402) (less)
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Pathogenic
(Jan 23, 2019)
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no assertion criteria provided
Method: literature only
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MACROCEPHALY, ACQUIRED, WITH IMPAIRED INTELLECTUAL DEVELOPMENT
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000882442.1
First in ClinVar: Jan 28, 2019 Last updated: Jan 28, 2019 |
Comment on evidence:
In a 7-year-old boy (P2) with acquired macrocephaly and impaired intellectual development (MACID; 618286), Schanze et al. (2018) identified heterozygosity for a c.265C-T transition (c.265C-T, … (more)
In a 7-year-old boy (P2) with acquired macrocephaly and impaired intellectual development (MACID; 618286), Schanze et al. (2018) identified heterozygosity for a c.265C-T transition (c.265C-T, NM_001190737.1) in exon 2 of the NFIB gene, resulting in arg89-to-ter (R89X) substitution. DNA from the father was not available for testing. The variant was not present in the dbSNP, 1000 Genomes Project, EVS, or ExAC databases. (less)
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Likely pathogenic
(Aug 25, 2019)
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no assertion criteria provided
Method: clinical testing
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Macrocephaly, acquired, with impaired intellectual development
Affected status: yes
Allele origin:
germline
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Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City
Accession: SCV001132950.1
First in ClinVar: Jan 04, 2020 Last updated: Jan 04, 2020 |
|
Comment:
Comment:
Variant summary: NFIB c.265C>T (p.Arg89X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 251404 control chromosomes (gnomAD). c.265C>T has been reported in the literature in at least one individual affected with macrocephaly, developmental delays, and mild-moderate intellectual disability (e.g. Schanze_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=1) and likely pathogenic/pathogenic (n=3). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32902921, 33130023, 30388402)
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:
This variant is interpreted as a Likely pathogenic for Macrocephaly, acquired, with impaired intellectual development, autosomal dominant. The following ACMG Tag(s) were applied: PM2, PVS1.
Comment:
Variant summary: NFIB c.265C>T (p.Arg89X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 251404 control chromosomes (gnomAD). c.265C>T has been reported in the literature in at least one individual affected with macrocephaly, developmental delays, and mild-moderate intellectual disability (e.g. Schanze_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=1) and likely pathogenic/pathogenic (n=3). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32902921, 33130023, 30388402)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| NFIB Haploinsufficiency Is Associated with Intellectual Disability and Macrocephaly. | Schanze I | American journal of human genetics | 2018 | PMID: 30388402 |
Text-mined citations for rs764333096 ...
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.