7-140739956-GA-GAA

Variant names:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_004333.6(BRAF):c.1993-11dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00012 in 1,605,482 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

BRAF
NM_004333.6 intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.100

Variant links:

Genes affected

BRAF (HGNC:1097): (B-Raf proto-oncogene, serine/threonine kinase) This gene encodes a protein belonging to the RAF family of serine/threonine protein kinases. This protein plays a role in regulating the MAP kinase/ERK signaling pathway, which affects cell division, differentiation, and secretion. Mutations in this gene, most commonly the V600E mutation, are the most frequently identified cancer-causing mutations in melanoma, and have been identified in various other cancers as well, including non-Hodgkin lymphoma, colorectal cancer, thyroid carcinoma, non-small cell lung carcinoma, hairy cell leukemia and adenocarcinoma of lung. Mutations in this gene are also associated with cardiofaciocutaneous, Noonan, and Costello syndromes, which exhibit overlapping phenotypes. A pseudogene of this gene has been identified on the X chromosome. [provided by RefSeq, Aug 2017]

BRAF links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP6

Variant 7-140739956-G-GA is Benign according to our data. Variant chr7-140739956-G-GA is described in ClinVar as [Likely_benign]. Clinvar id is 259289.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000139 (21/150822) while in subpopulation NFE AF= 0.000222 (15/67626). AF 95% confidence interval is 0.000136. There are 0 homozygotes in gnomad4. There are 11 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRAF	NM_001374258.1 link	c.2113-11dupT		intron_variant	Intron 17 of 19	ENST00000644969.2	NP_001361187.1
BRAF	NM_004333.6 link	c.1993-11dupT		intron_variant	Intron 16 of 17	ENST00000646891.2	NP_004324.2	P15056

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRAF	ENST00000644969.2 link	c.2113-11dupT		intron_variant	Intron 17 of 19		NM_001374258.1	ENSP00000496776.1		A0A2R8Y8E0
BRAF	ENST00000646891.2 link	c.1993-11dupT		intron_variant	Intron 16 of 17		NM_004333.6	ENSP00000493543.1		P15056

Frequencies

GnomAD3 genomes

AF:

0.000139

AC:

AN:

150822

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000122

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000983

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000222

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000118

AC:

171

AN:

1454660

Hom.:

Cov.:

AF XY:

0.000119

AC XY:

AN XY:

723824

show subpopulations

Gnomad4 AFR exome

AF:

0.000183

Gnomad4 AMR exome

AF:

0.000184

Gnomad4 ASJ exome

AF:

0.0000771

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000467

Gnomad4 FIN exome

AF:

0.0000572

Gnomad4 NFE exome

AF:

0.000124

Gnomad4 OTH exome

AF:

0.0000999

GnomAD4 genome

AF:

0.000139

AC:

AN:

150822

Hom.:

Cov.:

AF XY:

0.000150

AC XY:

AN XY:

73546

show subpopulations

Gnomad4 AFR

AF:

0.000122

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000983

Gnomad4 NFE

AF:

0.000222

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000128

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Nov 11, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BRAF c.1993-11dupT alters a non-conserved nucleotide located at a position not widely known to affect splicing. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00012 in 1605482 control chromosomes, predominantly at a frequency of 0.00015 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 32 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRAF causing Cardiofaciocutaneous Syndrome phenotype (4.7e-06). To our knowledge, no occurrence of c.1993-11dupT in individuals affected with Cardiofaciocutaneous Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 259289). Based on the evidence outlined above, the variant was classified as benign. -

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 22, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

c.1993-11_1993-10insT in intron 16 of BRAF: This variant is not expected to have clinical significance because an insertion of a T nucleotide at this position d oes not diverge from the splice consensus sequence and is therefore unlikely to impact splicing. It has been identified in 0.04% (26/62482) of European chromoso mes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; d bSNP rs765734118). -

not provided

Benign:1

Dec 03, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

RASopathy

Benign:1

Dec 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over