rs1042695

Positions:

• chr8-11564446-T-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001715.3(BLK):​c.*338T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00542 in 562,732 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0041 (5 hom., cov: 35)
  • Exomes 𝑓: 0.0059 (16 hom.)
• Consequence: BLK NM_001715.3 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:1
• Conservation: PhyloP100: -1.33

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 8-11564446-T-G is Benign according to our data. Variant chr8-11564446-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 12320.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}.
• BS2: High AC in GnomAd4 at 631 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BLK	NM_001715.3	c.*338T>G		3_prime_UTR_variant	13/13	ENST00000259089.9	NP_001706.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BLK	ENST00000259089.9	c.*338T>G		3_prime_UTR_variant	13/13	1	NM_001715.3	ENSP00000259089	P1
	ENST00000602626.2	n.77+172A>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00414 AC: 630 AN: 152228 Hom.: 5 Cov.: 35

Gnomad AFR AF: 0.00137

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00366

Gnomad ASJ AF: 0.0279

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00559

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00545

Gnomad OTH AF: 0.00717

GnomAD3 exomes AF: 0.00636 AC: 820 AN: 128888 Hom.: 5 AF XY: 0.00636 AC XY: 448 AN XY: 70456

Gnomad AFR exome AF: 0.00131

Gnomad AMR exome AF: 0.00411

Gnomad ASJ exome AF: 0.0264

Gnomad EAS exome AF: 0.000959

Gnomad SAS exome AF: 0.00810

Gnomad FIN exome AF: 0.000375

Gnomad NFE exome AF: 0.00592

Gnomad OTH exome AF: 0.00501

GnomAD4 exome AF: 0.00589 AC: 2419 AN: 410386 Hom.: 16 Cov.: 0 AF XY: 0.00615 AC XY: 1392 AN XY: 226162

Gnomad4 AFR exome AF: 0.00185

Gnomad4 AMR exome AF: 0.00404

Gnomad4 ASJ exome AF: 0.0270

Gnomad4 EAS exome AF: 0.000517

Gnomad4 SAS exome AF: 0.00763

Gnomad4 FIN exome AF: 0.000452

Gnomad4 NFE exome AF: 0.00521

Gnomad4 OTH exome AF: 0.00652

GnomAD4 genome AF: 0.00414 AC: 631 AN: 152346 Hom.: 5 Cov.: 35 AF XY: 0.00411 AC XY: 306 AN XY: 74500

Gnomad4 AFR AF: 0.00142

Gnomad4 AMR AF: 0.00366

Gnomad4 ASJ AF: 0.0279

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.00539

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00545

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00750 Hom.: 0

Bravo AF: 0.00436

Asia WGS AF: 0.00808 AC: 28 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Maturity-onset diabetes of the young type 11 Pathogenic:1 Benign:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 25, 2009	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	3.7
DANN	Benign	0.27

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

LitVar

Other links and lift over

dbSNP: rs1042695; hg19: chr8-11421955; COSMIC: COSV52056084; COSMIC: COSV52056084;