rs397507475

Positions:

• chr7-140778054-A-C
• chr7-140778054-A-G
• chr7-140778054-A-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Moderate

The NM_001374258.1(BRAF):​c.1574T>G​(p.Leu525Trp) 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L525F) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRAF NM_001374258.1 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.29

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 11 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 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 chr7-140778053-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 13975.Status of the report is reviewed_by_expert_panel, 3 stars.
• 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 4.9008 (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, 0.925
• PP5: Variant 7-140778054-A-C is Pathogenic according to our data. Variant chr7-140778054-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 1325840.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRAF	NM_001374258.1	c.1574T>G	p.Leu525Trp	missense_variant	13/20	ENST00000644969.2
BRAF	NM_004333.6	c.1454T>G	p.Leu485Trp	missense_variant	12/18	ENST00000646891.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRAF	ENST00000644969.2	c.1574T>G	p.Leu525Trp	missense_variant	13/20		NM_001374258.1
BRAF	ENST00000646891.2	c.1454T>G	p.Leu485Trp	missense_variant	12/18		NM_004333.6	P4
	ENST00000700122.1	n.502+3186A>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiofaciocutaneous syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Oct 11, 2021

This variant was identified as de novo (maternity and paternity confirmed)._x000D_ Criteria applied: PS2_MOD, PM1_MOD, PM5_STR, PM2_SUP, PP3 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	32
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.95	.;.;D;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.92	D;D;D;D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Uncertain	2.6	.;.;M;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-4.3	.;.;.;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	.;.;.;D
Polyphen		1.0	.;.;D;.
MutPred		0.76		Gain of MoRF binding (P = 0.0337);.;Gain of MoRF binding (P = 0.0337);.;
MVP		0.98
MPC		2.6
ClinPred		1.0	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.97
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-140477854; COSMIC: COSV56190001; COSMIC: COSV56190001;