VCV001805131.1 - ClinVar

NM_001190737.2(NFIB):c.93_94del (p.Trp31fs)

Germline

Classification

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.

(1)

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

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001190737.2(NFIB):c.93_94del (p.Trp31fs)

Variation ID: 1805131 Accession: VCV001805131.1

Type and length

Deletion, 2 bp

Location

Cytogenetic: 9p22.3 9: 14307457-14307458 (GRCh38) [ NCBI UCSC ] 9: 14307456-14307457 (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	Dec 24, 2022	Dec 24, 2022	Feb 2, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_001190737.2:c.93_94del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001177666.1:p.Trp31fs	frameshift
NM_001190738.2:c.171_172del	NP_001177667.1:p.Trp57fs	frameshift
NM_001369458.1:c.159_160del	NP_001356387.1:p.Trp53fs	frameshift
NM_001369459.1:c.159_160del	NP_001356388.1:p.Trp53fs	frameshift
NM_001369460.1:c.81_82del	NP_001356389.1:p.Trp27fs	frameshift
NM_001369461.1:c.93_94del	NP_001356390.1:p.Trp31fs	frameshift
NM_001369462.1:c.159_160del	NP_001356391.1:p.Trp53fs	frameshift
NM_001369463.1:c.81_82del	NP_001356392.1:p.Trp27fs	frameshift
NM_001369464.1:c.93_94del	NP_001356393.1:p.Trp31fs	frameshift
NM_001369465.1:c.66_67del	NP_001356394.1:p.Trp22fs	frameshift
NM_001369466.1:c.81_82del	NP_001356395.1:p.Trp27fs	frameshift
NM_001369467.1:c.66_67del	NP_001356396.1:p.Trp22fs	frameshift
NM_001369468.1:c.159_160del	NP_001356397.1:p.Trp53fs	frameshift
NM_001369469.1:c.-52_-51del		5 prime UTR
NM_001369470.1:c.81_82del	NP_001356399.1:p.Trp27fs	frameshift
NM_001369471.1:c.93_94del	NP_001356400.1:p.Trp31fs	frameshift
NM_001369472.1:c.81_82del	NP_001356401.1:p.Trp27fs	frameshift
NM_001369473.1:c.81_82del	NP_001356402.1:p.Trp27fs	frameshift
NM_001369474.1:c.78_79del	NP_001356403.1:p.Trp26fs	frameshift
NM_001369475.1:c.93_94del	NP_001356404.1:p.Trp31fs	frameshift
NM_001369476.1:c.66_67del	NP_001356405.1:p.Trp22fs	frameshift
NM_001369477.1:c.93_94del	NP_001356406.1:p.Trp31fs	frameshift
NM_001369478.1:c.81_82del	NP_001356407.1:p.Trp27fs	frameshift
NM_001369481.1:c.93_94del	NP_001356410.1:p.Trp31fs	frameshift
NM_005596.3:c.93_94del	NP_005587.2:p.Trp31fs	frameshift
NC_000009.12:g.14307457_14307458del
NC_000009.11:g.14307456_14307457del

... more HGVS ... less HGVS

Protein change

W22fs, W26fs, W27fs, W31fs, W53fs, W57fs

Other names

Canonical SPDI

NC_000009.12:14307456:AC:

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Links

VarSome

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
Gene	OMIM	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.
Macrocephaly, acquired, with impaired intellectual development	Pathogenic (1)	criteria provided, single submitter	Feb 2, 2022	RCV002471549.1

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.
Pathogenic (Feb 02, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Macrocephaly, acquired, with impaired intellectual development (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002768299.1 First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022	Publications: PubMed (1) PubMed: 30388402 Comment: Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. 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 Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with acquired macrocephaly with impaired intellectual development (MIM#618286). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0702 - Other premature termination variants comparable to the one identified in this case have strong previous evidence for pathogenicity. Seven NMD-predicted variants have been reported as likely pathogenic in ClinVar, and in individuals with intellectual disability and macrocephaly (PMID: 30388402). However, two NMD-predicted variants have been reported as a VUS in affected individuals (DECIPHER, ClinVar), and one as a VUS and likely benign (ClinVar). (SP) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1205 - This variant has been shown to be maternally inherited (trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)

Comment:

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with acquired macrocephaly with impaired intellectual development (MIM#618286). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0702 - Other premature termination variants comparable to the one identified in this case have strong previous evidence for pathogenicity. Seven NMD-predicted variants have been reported as likely pathogenic in ClinVar, and in individuals with intellectual disability and macrocephaly (PMID: 30388402). However, two NMD-predicted variants have been reported as a VUS in affected individuals (DECIPHER, ClinVar), and one as a VUS and likely benign (ClinVar). (SP) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1205 - This variant has been shown to be maternally inherited (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:

Citations for germline classification of this variant

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 this variant ...

Record last updated Dec 24, 2022

ClinVar Genomic variation as it relates to human health

NM_001190737.2(NFIB):c.93_94del (p.Trp31fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...