rs4841557

Variant names:

• chr8-11558063-A-G
• rs4841557
• NM_001715.3:c.1029+25A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001715.3(BLK):​c.1029+25A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.583 in 1,611,546 control chromosomes in the GnomAD database, including 283,195 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.58 (26267 hom., cov: 33)
  • Exomes 𝑓: 0.58 (256928 hom.)
• Consequence: BLK NM_001715.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0200
• Publications: 11 publications found

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-AS1 (HGNC:58190):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 8-11558063-A-G is Benign according to our data. Variant chr8-11558063-A-G is described in ClinVar as Benign. ClinVar VariationId is 1182428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.624 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BLK	NM_001715.3	c.1029+25A>G		intron_variant	Intron 10 of 12	ENST00000259089.9	NP_001706.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BLK	ENST00000259089.9	c.1029+25A>G		intron_variant	Intron 10 of 12	1	NM_001715.3	ENSP00000259089.4

Frequencies

GnomAD3 genomes AF: 0.575 AC: 87393 AN: 151944 Hom.: 26250 Cov.: 33

Gnomad AFR AF: 0.630

Gnomad AMI AF: 0.398

Gnomad AMR AF: 0.465

Gnomad ASJ AF: 0.654

Gnomad EAS AF: 0.0587

Gnomad SAS AF: 0.434

Gnomad FIN AF: 0.553

Gnomad MID AF: 0.646

Gnomad NFE AF: 0.618

Gnomad OTH AF: 0.560

GnomAD2 exomes AF: 0.521 AC: 130680 AN: 250634 AF XY: 0.524

Gnomad AFR exome AF: 0.639

Gnomad AMR exome AF: 0.375

Gnomad ASJ exome AF: 0.660

Gnomad EAS exome AF: 0.0604

Gnomad FIN exome AF: 0.567

Gnomad NFE exome AF: 0.619

Gnomad OTH exome AF: 0.565

GnomAD4 exome AF: 0.583 AC: 851439 AN: 1459484 Hom.: 256928 Cov.: 32 AF XY: 0.581 AC XY: 422173 AN XY: 726120

African (AFR) AF: 0.644 AC: 21522 AN: 33434

American (AMR) AF: 0.383 AC: 17085 AN: 44646

Ashkenazi Jewish (ASJ) AF: 0.660 AC: 17214 AN: 26096

East Asian (EAS) AF: 0.0572 AC: 2268 AN: 39668

South Asian (SAS) AF: 0.457 AC: 39395 AN: 86182

European-Finnish (FIN) AF: 0.570 AC: 30395 AN: 53308

Middle Eastern (MID) AF: 0.617 AC: 3538 AN: 5734

European-Non Finnish (NFE) AF: 0.618 AC: 685809 AN: 1110130

Other (OTH) AF: 0.568 AC: 34213 AN: 60286

GnomAD4 genome AF: 0.575 AC: 87451 AN: 152062 Hom.: 26267 Cov.: 33 AF XY: 0.564 AC XY: 41900 AN XY: 74320

African (AFR) AF: 0.630 AC: 26146 AN: 41482

American (AMR) AF: 0.464 AC: 7087 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.654 AC: 2270 AN: 3470

East Asian (EAS) AF: 0.0585 AC: 303 AN: 5180

South Asian (SAS) AF: 0.435 AC: 2097 AN: 4818

European-Finnish (FIN) AF: 0.553 AC: 5841 AN: 10564

Middle Eastern (MID) AF: 0.637 AC: 186 AN: 292

European-Non Finnish (NFE) AF: 0.618 AC: 41989 AN: 67950

Other (OTH) AF: 0.553 AC: 1169 AN: 2114

Alfa AF: 0.618 Hom.: 5481

Bravo AF: 0.565

Asia WGS AF: 0.279 AC: 974 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	3.8
DANN	Benign	0.66
PhyloP100		0.020
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4841557; hg19: chr8-11415572; COSMIC: COSV52049361; COSMIC: COSV52049361;