Genetic Variant NM_001715.3:c.843T>G (chr8-11556728-T-G) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001715.3(BLK):c.843T>G(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. Variant has been reported in ClinVar as association (no stars). 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

Scores

Clinical Significance

association no assertion criteria provided O:1

Conservation

PhyloP100: 1.35

Publications

30 publications found

Variant links:

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 Gene-Disease associations (from GenCC):

maturity-onset diabetes of the young
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
systemic lupus erythematosus
Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet
maturity-onset diabetes of the young type 11
Inheritance: AD, Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
monogenic diabetes
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

BLK links:

ENSG00000269954 (HGNC:58190):

ENSG00000269954 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.963

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001715.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BLK	NM_001715.3	MANE Select	c.843T>G	p.Phe281Leu	missense	Exon 9 of 13	NP_001706.2
	BLK	NM_001330465.2		c.630T>G	p.Phe210Leu	missense	Exon 8 of 12	NP_001317394.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
BLK	ENST00000259089.9	TSL:1 MANE Select	c.843T>G	p.Phe281Leu	missense	Exon 9 of 13	ENSP00000259089.4
BLK	ENST00000526778.1	TSL:3	n.640T>G		non_coding_transcript_exon	Exon 4 of 4
BLK	ENST00000645242.1		n.994T>G		non_coding_transcript_exon	Exon 8 of 12

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: association

Submissions summary: Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Systemic lupus erythematosus

Other:1

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance:association

Review Status:no assertion criteria provided

Collection Method:research

BLK gene locus is associated with Systemic lupus erythematosus, sjogren's syndrome and other systemic inflammatory conditions.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.060

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.55

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.47

FATHMM_MKL

Benign

0.70

LIST_S2

Pathogenic

0.98

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.96

MetaSVM

Uncertain

0.14

MutationAssessor

Benign

1.1

PhyloP100

1.3

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-5.3

REVEL

Pathogenic

0.67

Sift

Uncertain

0.0090

Sift4G

Uncertain

0.037

Polyphen

0.99

Vest4

0.87

MutPred

0.82

Loss of catalytic residue at M276 (P = 0.0456)

MVP

0.93

MPC

0.17

ClinPred

0.99

GERP RS

0.64

Varity_R

0.40

gMVP

0.74

Mutation Taster

=38/62

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over