VCV000040391.37 - ClinVar

NM_004333.6(BRAF):c.1929A>G (p.Gly643=)

Germline

Top reviewed classifications are shown here.

Submission summary:

15 submissions

14 submitters

6 conditions

Reviewed by expert panel

Benign

Apr 2017 by ClinGen RASopa… FDA Recognized Database

for Noonan syndrome and Noonan-related syndrome

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_004333.6(BRAF):c.1929A>G (p.Gly643=)

Variation ID: 40391 Accession: VCV000040391.37

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7q34 7: 140749350 (GRCh38) [ NCBI UCSC ] 7: 140449150 (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 16, 2015	Sep 29, 2024	Apr 18, 2017

HGVS

Nucleotide	Protein	Molecular consequence
NM_004333.6:c.1929A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_004324.2:p.Gly643=	synonymous
NM_001374258.1:c.2049A>G MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001361187.1:p.Gly683=	synonymous
NM_001354609.2:c.1929A>G	NP_001341538.1:p.Gly643=	synonymous
NM_001374244.1:c.2049A>G	NP_001361173.1:p.Gly683=	synonymous
NM_001378467.1:c.1938A>G	NP_001365396.1:p.Gly646=	synonymous
NM_001378468.1:c.1929A>G	NP_001365397.1:p.Gly643=	synonymous
NM_001378469.1:c.1863A>G	NP_001365398.1:p.Gly621=	synonymous
NM_001378470.1:c.1827A>G	NP_001365399.1:p.Gly609=	synonymous
NM_001378471.1:c.1818A>G	NP_001365400.1:p.Gly606=	synonymous
NM_001378472.1:c.1773A>G	NP_001365401.1:p.Gly591=	synonymous
NM_001378473.1:c.1773A>G	NP_001365402.1:p.Gly591=	synonymous
NM_001378474.1:c.1929A>G	NP_001365403.1:p.Gly643=	synonymous
NM_001378475.1:c.1665A>G	NP_001365404.1:p.Gly555=	synonymous
NC_000007.14:g.140749350T>C
NC_000007.13:g.140449150T>C
NG_007873.3:g.180415A>G
LRG_299:g.180415A>G
LRG_299t1:c.1929A>G

... more HGVS ... less HGVS

Protein change

Other names

p.G643G
p.G643G:GGA>GGG
NM_004333.4(BRAF):c.1929A>G

Canonical SPDI

NC_000007.14:140749349: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.

0.35104 (C)

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.20144

Exome Aggregation Consortium (ExAC) 0.21236

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.32001

1000 Genomes Project 0.35104

1000 Genomes Project 30x 0.35587

The Genome Aggregation Database (gnomAD) 0.30796

Trans-Omics for Precision Medicine (TOPMed) 0.31557

Links

ClinGen: CA135110 dbSNP: rs9648696 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.
BRAF		Little evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	1254	1368

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.
RASopathy	Benign (4)	reviewed by expert panel	Apr 18, 2017	RCV000033338.25
not specified	Benign (5)	criteria provided, multiple submitters, no conflicts	Nov 16, 2017	RCV000037940.31
Noonan syndrome 7	Benign (1)	criteria provided, single submitter	Jan 13, 2018	RCV000306807.13
LEOPARD syndrome 3	Benign (1)	criteria provided, single submitter	Jan 13, 2018	RCV000361471.13
not provided	Benign (3)	criteria provided, multiple submitters, no conflicts	Nov 29, 2023	RCV000509253.22
Cardiovascular phenotype	Benign (1)	criteria provided, single submitter	Dec 4, 2018	RCV002408490.9

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.
Benign (Apr 18, 2017)	reviewed by expert panel (ClinGen RASopathy ACMG Specifications v1) Method: curation	Noonan syndrome and Noonan-related syndrome (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	ClinGen RASopathy Variant Curation Expert Panel FDA Recognized Database Accession: SCV000616456.4 First in ClinVar: Dec 19, 2017 Last updated: Dec 11, 2022	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/043632b0-38d9-48f7-b0b4-993f0aa553b4 Comment: The filtering allele frequency of the c.1929A>G (p.Gly643=) variant in the BRAF gene is 66.117% (6984/10356) of African chromosomes by the Exome Aggregation Consortium, which … (more) The filtering allele frequency of the c.1929A>G (p.Gly643=) variant in the BRAF gene is 66.117% (6984/10356) of African chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) (less)
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	NOT SPECIFIED Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000310111.1 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016
Benign (Feb 01, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	RASopathy Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001000055.6 First in ClinVar: Dec 17, 2019 Last updated: Feb 20, 2024
Benign (Nov 29, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV001158928.8 First in ClinVar: Feb 10, 2020 Last updated: Feb 20, 2024
Benign (Jan 24, 2012)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Rasopathy Affected status: yes Allele origin: germline	GeneDx Accession: SCV000057243.4 First in ClinVar: Jul 03, 2013 Last updated: May 27, 2015	Comment: The variant is found in NOONAN panel(s).
Benign (May 19, 2015)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000058308.9 First in ClinVar: Apr 04, 2013 Last updated: Oct 02, 2016	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=BRAF Number of individuals with the variant: 4 Sex: mixed
Benign (Nov 16, 2017)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000918664.1 First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019	Comment: Variant summary: The BRAF c.1929A>G (p.Gly643Gly) variant involves the alteration of a nucleotide, resulting in a synonymous change. One in silico tool predicts a polymorphism … (more) Variant summary: The BRAF c.1929A>G (p.Gly643Gly) variant involves the alteration of a nucleotide, resulting in a synonymous change. One in silico tool predicts a polymorphism outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant does not affect any ESE site. However, these predictions have yet to be confirmed by functional studies. This variant was found in 25661/120836 control chromosomes at a frequency of 0.2123622, which is approximately 84945 times the estimated maximal expected allele frequency of a pathogenic BRAF variant (0.0000025), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign. (less)
Benign (Dec 03, 2007)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000061605.5 First in ClinVar: May 03, 2013 Last updated: Oct 02, 2016	Number of individuals with the variant: 1113
Benign (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Noonan syndrome 7 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000466968.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
Benign (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	LEOPARD syndrome 3 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000466969.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
Benign (Dec 04, 2018)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002720704.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Comment: This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more) This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005270690.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Benign (-)	no assertion criteria provided Method: clinical testing	Rasopathy Affected status: yes Allele origin: unknown	Baylor Genetics Accession: SCV000196685.1 First in ClinVar: Jan 16, 2015 Last updated: Jan 16, 2015	Comment: Variant classified using ACMG guidelines
Benign (Jan 15, 2015)	no assertion criteria provided Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center Accession: SCV000207628.1 First in ClinVar: Feb 19, 2015 Last updated: Feb 19, 2015
not provided (-)	no classification provided Method: phenotyping only	Not Provided Affected status: unknown Allele origin: unknown	GenomeConnect, ClinGen Accession: SCV000607337.1 First in ClinVar: Oct 16, 2017 Last updated: Oct 16, 2017	Comment: GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical … (more) GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less) Clinical Features: Prenatal maternal abnormality (present) , Abnormal delivery (present) , Abnormality of the skull (present) , Abnormality of the nose (present) , Abnormality of the neck … (more) Prenatal maternal abnormality (present) , Abnormal delivery (present) , Abnormality of the skull (present) , Abnormality of the nose (present) , Abnormality of the neck (present) , Abnormality of the oral cavity (present) , Abnormality of the hair (present) , Hearing impairment (present) , Aplasia/Hypoplasia of the ear (present) , Short attention span (present) , Generalized abnormality of skin (present) , Joint hypermobility (present) , Abnormality of the large intestine (present) , Abnormality of esophagus morphology (present) (less) Age: 0-9 years Sex: male Testing laboratory: PreventionGenetics,PreventionGenetics Date variant was reported to submitter: 2014-10-27 Testing laboratory interpretation: Benign
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Comment:

The filtering allele frequency of the c.1929A>G (p.Gly643=) variant in the BRAF gene is 66.117% (6984/10356) of African chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581)

Comment:

Variant summary: The BRAF c.1929A>G (p.Gly643Gly) variant involves the alteration of a nucleotide, resulting in a synonymous change. One in silico tool predicts a polymorphism outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant does not affect any ESE site. However, these predictions have yet to be confirmed by functional studies. This variant was found in 25661/120836 control chromosomes at a frequency of 0.2123622, which is approximately 84945 times the estimated maximal expected allele frequency of a pathogenic BRAF variant (0.0000025), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign.

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Comment:

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=BRAF	-	-	-	-
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/043632b0-38d9-48f7-b0b4-993f0aa553b4	-	-	-	-

Text-mined citations for rs9648696 ...

These 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

ClinVar Genomic variation as it relates to human health

NM_004333.6(BRAF):c.1929A>G (p.Gly643=)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs9648696 ...