rs2306234

chr8-11556728-T-Achr8-11556728-T-Cchr8-11556728-T-G

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. Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein 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]

(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	UniProt
BLK	NM_001715.3	c.843T>A	p.Phe281Leu	missense_variant	9/13	ENST00000259089.9
LOC105379241	XR_948956.3	n.377-67A>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BLK	ENST00000259089.9	c.843T>A	p.Phe281Leu	missense_variant	9/13	1	NM_001715.3	P1
	ENST00000602626.2	n.331-67A>T		intron_variant, non_coding_transcript_variant

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
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Uncertain	0.14	D
MutationTaster	Benign	0.00027	P;P
PrimateAI	Uncertain	0.74	T
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;