rs397516892

Positions:

• chr7-140778066-G-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_004333.6(BRAF):​c.1442C>A​(p.Ala481Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRAF NM_004333.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.96

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]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PM1: In a domain Protein kinase (size 260) in uniprot entity BRAF_HUMAN there are 21 pathogenic changes around while only 1 benign (95%) in NM_004333.6
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), BRAF. . Gene score misZ 3.7208 (greater than the threshold 3.09). Trascript score misZ 4.9447 (greater than threshold 3.09). GenCC has associacion of gene with LEOPARD syndrome 3, anaplastic astrocytoma, Noonan syndrome with multiple lentigines, cardiofaciocutaneous syndrome 1, Noonan syndrome, cardiofaciocutaneous syndrome, Costello syndrome, Noonan syndrome 7.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.933
• PP5: Variant 7-140778066-G-T is Pathogenic according to our data. Variant chr7-140778066-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 44805.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-140778066-G-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRAF	NM_001374258.1	c.1562C>A	p.Ala521Glu	missense_variant	13/20	ENST00000644969.2	NP_001361187.1
BRAF	NM_004333.6	c.1442C>A	p.Ala481Glu	missense_variant	12/18	ENST00000646891.2	NP_004324.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRAF	ENST00000644969.2	c.1562C>A	p.Ala521Glu	missense_variant	13/20		NM_001374258.1	ENSP00000496776
BRAF	ENST00000646891.2	c.1442C>A	p.Ala481Glu	missense_variant	12/18		NM_004333.6	ENSP00000493543	P4
	ENST00000700122.1	n.502+3198G>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurodevelopmental delay Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

-

- -

Cardiofaciocutaneous syndrome 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

3billion

Mar 22, 2022

Same nucleotide change resulting in same amino acid change has been previously reported to be associated with [GeneName] related disorder (ClinVar ID: VCV000044805, PMID:24800029). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000636502). The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.99>=0.6). A missense variant is a common mechanism . It is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Cardio-facio-cutaneous syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 29, 2012

The Ala481Glu variant has not been reported in the literature nor previously ide ntified by our laboratory. This variant was not identified in either parent of t his individual; therefore, the variant has likely occurred de novo in this indiv idual, assuming that non-medical explanations including alternate paternity or u ndisclosed adoption have been ruled out. Computational analyses (biochemical am ino acid properties, conservation, PolyPhen2, SIFT, AlignGVGD) suggest that the Ala481Gln variant may impact the protein. In addition, this variant occurs with in the functionally important ATP binding pocket of the BRAF tyrosine kinase dom ain. In summary, this variant is likely to be pathogenic although further studi es could help establish the pathogenicity of this variant. The presence of a he terozygous pathogenic variant in BRAF is consistent with a diagnosis of cardio-f acio-cutaneous syndrome but this information should be reconciled with the compl ete clinical history of this individual. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.96	.;.;D;.
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	D;D;D;D
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.93	D;D;D;D
MetaSVM	Uncertain	0.28	D
MutationAssessor	Uncertain	2.2	.;.;M;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.93	D
REVEL	Pathogenic	0.99
Polyphen		1.0	.;.;D;.
MutPred		0.71		Loss of sheet (P = 0.0025);.;Loss of sheet (P = 0.0025);.;
MVP		1.0
MPC		2.2
ClinPred		1.0	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.99

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

Other links and lift over

dbSNP: rs397516892; hg19: chr7-140477866;