rs397507458

Positions:

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP3BP6BS1BS2

The NM_001374258.1(BRAF):c.89_100del(p.Gly30_Ala33del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000432 in 1,528,870 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G30G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000033 ( 0 hom. )

Consequence

BRAF
NM_001374258.1 inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: 0.782

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 -10 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001374258.1

BP6

Variant 7-140924603-GCGGCGCCGGCGC-G is Benign according to our data. Variant chr7-140924603-GCGGCGCCGGCGC-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 40222.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000139 (21/151506) while in subpopulation AFR AF= 0.000484 (20/41306). AF 95% confidence interval is 0.000321. There are 0 homozygotes in gnomad4. There are 10 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd4 at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRAF	NM_001374258.1 linkuse as main transcript	c.89_100del	p.Gly30_Ala33del	inframe_deletion	1/20	ENST00000644969.2
BRAF	NM_004333.6 linkuse as main transcript	c.89_100del	p.Gly30_Ala33del	inframe_deletion	1/18	ENST00000646891.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRAF	ENST00000644969.2 linkuse as main transcript	c.89_100del	p.Gly30_Ala33del	inframe_deletion	1/20		NM_001374258.1
BRAF	ENST00000646891.2 linkuse as main transcript	c.89_100del	p.Gly30_Ala33del	inframe_deletion	1/18		NM_004333.6	P4

Frequencies

GnomAD3 genomes

AF:

0.000139

AC:

AN:

151506

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000484

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000148

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000317

AC:

AN:

126314

Hom.:

AF XY:

0.0000144

AC XY:

AN XY:

69262

show subpopulations

Gnomad AFR exome

AF:

0.000693

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000327

AC:

AN:

1377364

Hom.:

AF XY:

0.0000338

AC XY:

AN XY:

679568

show subpopulations

Gnomad4 AFR exome

AF:

0.000354

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000845

Gnomad4 SAS exome

AF:

0.0000380

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000232

Gnomad4 OTH exome

AF:

0.0000522

GnomAD4 genome

AF:

0.000139

AC:

AN:

151506

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

73986

show subpopulations

Gnomad4 AFR

AF:

0.000484

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000148

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000728

Hom.:

Bravo

AF:

0.000170

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

RASopathy

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Dec 12, 2023	This variant, c.89_100del, results in the deletion of 4 amino acid(s) of the BRAF protein (p.Gly30_Ala33del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs397507458, gnomAD 0.05%). This variant has been observed in individual(s) with clinical features of BRAF-related conditions (PMID: 29907801). ClinVar contains an entry for this variant (Variation ID: 40222). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 29, 2014	c.89_100del12: p.Gly30_Ala33delGlyAlaGlyAla (G30_A33delGAGA) in exon 1 of the BRAF gene (NM_004333.4)The c.89_100del12 in-frame deletion in the BRAF gene has not been reported as a disease-causing mutation, nor is it known to be a benign polymorphism to our knowledge. This deletion occurs in a region of the protein that is not highly conserved in mammals and no disease-causing mutation has been reported before codon Threonine 241. Most disease-causing mutations result in a gain-of-function. It is uncertain if this deletion would result in a gain-of-function, loss-of-function, or have no impact on protein function at all. Therefore, this variant cannot be interpreted for diagnosis or used for genetic counseling without further studies. The variant is found in NOONAN panel(s). -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Mar 20, 2017

Variant summary: The BRAF c.89_100delGCGCCGGCGCCG (p.Gly30_Ala33del) variant causes an in-frame deletion. This variant is absent in 10494 control chromosomes (ExAC), but was present in 1/10568 chromosomes when filtered (non-PASS) variants were included. The variant of interest has not, to our knowledge, been reported in affected individuals via publications, nor evaluated for functional implications by in vivo/vitro studies. A clinical diagnostic laboratory classifies the variant as "uncertain significance." Therefore, the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)," until additional information (ie, clinical and functional studies) become available. -

BRAF-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 27, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Noonan syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Sep 22, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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