8-11556728-T-A

Position:

• chr8-11556728-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001715.3(BLK):​c.843T>A​(p.Phe281Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. F281F) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BLK NM_001715.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.35

Genes affected

BLK (HGNC:1057): (BLK proto-oncogene, Src family tyrosine kinase) This gene encodes a nonreceptor tyrosine-kinase of the src family of proto-oncogenes that are typically involved in cell proliferation and differentiation. The protein has a role in B-cell receptor signaling and B-cell development. The protein also stimulates insulin synthesis and secretion in response to glucose and enhances the expression of several pancreatic beta-cell transcription factors. [provided by RefSeq, Aug 2010]

BLK (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.961

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BLK	NM_001715.3	c.843T>A	p.Phe281Leu	missense_variant	9/13	ENST00000259089.9	NP_001706.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BLK	ENST00000259089.9	c.843T>A	p.Phe281Leu	missense_variant	9/13	1	NM_001715.3	ENSP00000259089.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 72

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D;D;D
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.69	D
LIST_S2	Pathogenic	0.98	.;D;.
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Uncertain	0.14	D
MutationAssessor	Benign	1.1	.;L;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-5.3	.;D;D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0090	.;D;D
Sift4G	Uncertain	0.037	.;D;D
Polyphen		0.99	.;D;.
Vest4		0.87, 0.80
MutPred		0.82		.;Loss of catalytic residue at M276 (P = 0.0456);.;
MVP		0.93
MPC		0.17
ClinPred		0.99	D
GERP RS		0.64
Varity_R		0.40
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2306234; hg19: chr8-11414237;