NM_001374258.1:c.1511G>C

Variant names:

• chr7-140781617-C-G
• rs121913348
• NM_001374258.1:c.1511G>C

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_001374258.1(BRAF):​c.1511G>C​(p.Gly504Ala) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G504E) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRAF NM_001374258.1 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.89

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]

ENSG00000289788 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_001374258.1
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-140781617-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 13964.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP2: Missense variant in the BRAF gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 139 curated pathogenic missense variants (we use a threshold of 10). The gene has 21 curated benign missense variants. Gene score misZ: 3.7208 (above the threshold of 3.09). Trascript score misZ: 4.9008 (above the threshold of 3.09). GenCC associations: The gene is linked to 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, 0.984
• PP5: Variant 7-140781617-C-G is Pathogenic according to our data. Variant chr7-140781617-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 40365.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRAF	NM_001374258.1	c.1511G>C	p.Gly504Ala	missense_variant	Exon 12 of 20	ENST00000644969.2	NP_001361187.1
BRAF	NM_004333.6	c.1391G>C	p.Gly464Ala	missense_variant	Exon 11 of 18	ENST00000646891.2	NP_004324.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRAF	ENST00000644969.2	c.1511G>C	p.Gly504Ala	missense_variant	Exon 12 of 20		NM_001374258.1	ENSP00000496776.1
BRAF	ENST00000646891.2	c.1391G>C	p.Gly464Ala	missense_variant	Exon 11 of 18		NM_004333.6	ENSP00000493543.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiofaciocutaneous syndrome 1 Pathogenic:1

Jan 03, 2022

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Same nucleotide change resulting in same amino acid change has been previously reported to be associated with BRAF related disorder (ClinVar ID: VCV000040365, PS1_P). Different missense changes at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013964,VCV000040364,VCV000279992,VCV000372572, PM5_M). The variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.895, PP3_P). A missense variant is a common mechanism associated with Cardiofaciocutaneous syndrome (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Cardio-facio-cutaneous syndrome Pathogenic:1

-

Service de Génétique Moléculaire, Hôpital Robert Debré

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	.;.;D;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D;D;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Uncertain	0.79	D
MutationAssessor	Benign	1.9	.;.;L;.
PrimateAI	Pathogenic	0.85	D
REVEL	Pathogenic	0.90
Polyphen		0.85	.;.;P;.
MutPred		0.97		Gain of MoRF binding (P = 0.0994);.;Gain of MoRF binding (P = 0.0994);.;
MVP		0.99
MPC		2.1
ClinPred		0.99	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.79

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: rs121913348; hg19: chr7-140481417;