VCV001806041.1 - ClinVar

NM_001190737.2(NFIB):c.340A>G (p.Lys114Glu)

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.

Likely 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.340A>G (p.Lys114Glu)

Variation ID: 1806041 Accession: VCV001806041.1

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 9p22.3 9: 14307211 (GRCh38) [ NCBI UCSC ] 9: 14307210 (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	Jun 11, 2020

HGVS

Nucleotide	Protein	Molecular consequence
NM_001190737.2:c.340A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001177666.1:p.Lys114Glu	missense
NM_001190738.2:c.418A>G	NP_001177667.1:p.Lys140Glu	missense
NM_001369458.1:c.406A>G	NP_001356387.1:p.Lys136Glu	missense
NM_001369459.1:c.406A>G	NP_001356388.1:p.Lys136Glu	missense
NM_001369460.1:c.328A>G	NP_001356389.1:p.Lys110Glu	missense
NM_001369461.1:c.340A>G	NP_001356390.1:p.Lys114Glu	missense
NM_001369462.1:c.406A>G	NP_001356391.1:p.Lys136Glu	missense
NM_001369463.1:c.328A>G	NP_001356392.1:p.Lys110Glu	missense
NM_001369464.1:c.340A>G	NP_001356393.1:p.Lys114Glu	missense
NM_001369465.1:c.313A>G	NP_001356394.1:p.Lys105Glu	missense
NM_001369466.1:c.328A>G	NP_001356395.1:p.Lys110Glu	missense
NM_001369467.1:c.313A>G	NP_001356396.1:p.Lys105Glu	missense
NM_001369468.1:c.406A>G	NP_001356397.1:p.Lys136Glu	missense
NM_001369469.1:c.196A>G	NP_001356398.1:p.Lys66Glu	missense
NM_001369470.1:c.325+3A>G		intron variant
NM_001369471.1:c.340A>G	NP_001356400.1:p.Lys114Glu	missense
NM_001369472.1:c.328A>G	NP_001356401.1:p.Lys110Glu	missense
NM_001369473.1:c.328A>G	NP_001356402.1:p.Lys110Glu	missense
NM_001369474.1:c.325A>G	NP_001356403.1:p.Lys109Glu	missense
NM_001369475.1:c.337+3A>G		intron variant
NM_001369476.1:c.313A>G	NP_001356405.1:p.Lys105Glu	missense
NM_001369477.1:c.340A>G	NP_001356406.1:p.Lys114Glu	missense
NM_001369478.1:c.325+3A>G		intron variant
NM_001369481.1:c.340A>G	NP_001356410.1:p.Lys114Glu	missense
NM_005596.3:c.340A>G	NP_005587.2:p.Lys114Glu	missense
NC_000009.12:g.14307211T>C
NC_000009.11:g.14307210T>C

... more HGVS ... less HGVS

Protein change

K105E, K109E, K110E, K114E, K136E, K140E, K66E

Other names

Canonical SPDI

NC_000009.12:14307210:T:C

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	Likely pathogenic (1)	criteria provided, single submitter	Jun 11, 2020	RCV002470325.1

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.
Likely pathogenic (Jun 11, 2020)	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: SCV002767082.1 First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022	Publications: PubMed (1) PubMed: 30388402 Comment: Based on the classification scheme VCGS_Germline_v0.6.1, this variant is classified as Likely Pathogenic. Following criteria are met: 0102 - Loss of function is a known … (more) Based on the classification scheme VCGS_Germline_v0.6.1, this variant is classified as Likely Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease for this gene. 0107 - This gene is known to be associated with autosomal dominant disease. 0200 - Variant is predicted to result in a heterozygous missense amino acid change from lysine to glutamic acid (exon 2). 0301 - Variant is absent from gnomAD. 0501 - Missense variant consistently predicted to be damaging by in silico tools or highly conserved with a major amino acid change. 0600 - Variant is located in an annotated domain or motif that does not have a well established function (MH1 domain; NCBI, PDB). 0704 - Comparable variant in relevant codon/region has low previous evidence for pathogenicity. An alternate change to threonine at the same residue has previously been described at pathogenic (ClinVar, PMID: 30388402). 0807 - Variant has not previously been reported in a clinical context. 0905 - No published segregation evidence has been identified for this variant. 1007 - No published functional evidence has been identified for this variant. 1204 - De Novo Variant (Parental status not tested but assumed). (less)

Comment:

Based on the classification scheme VCGS_Germline_v0.6.1, this variant is classified as Likely Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease for this gene. 0107 - This gene is known to be associated with autosomal dominant disease. 0200 - Variant is predicted to result in a heterozygous missense amino acid change from lysine to glutamic acid (exon 2). 0301 - Variant is absent from gnomAD. 0501 - Missense variant consistently predicted to be damaging by in silico tools or highly conserved with a major amino acid change. 0600 - Variant is located in an annotated domain or motif that does not have a well established function (MH1 domain; NCBI, PDB). 0704 - Comparable variant in relevant codon/region has low previous evidence for pathogenicity. An alternate change to threonine at the same residue has previously been described at pathogenic (ClinVar, PMID: 30388402). 0807 - Variant has not previously been reported in a clinical context. 0905 - No published segregation evidence has been identified for this variant. 1007 - No published functional evidence has been identified for this variant. 1204 - De Novo Variant (Parental status not tested but assumed).

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.340A>G (p.Lys114Glu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...