rs1042701

Variant names:

• chr8-11564536-G-A
• rs1042701
• ENST00000526097.1:n.1886G>A

Variant summary

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

The ENST00000526097.1(BLK):​n.1886G>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.379 in 477,818 control chromosomes in the GnomAD database, including 38,815 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (10731 hom., cov: 36)
  • Exomes 𝑓: 0.39 (28084 hom.)
• Consequence: BLK ENST00000526097.1 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0950
• Publications: 14 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

ENSG00000269954 (HGNC:58190):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 8-11564536-G-A is Benign according to our data. Variant chr8-11564536-G-A is described in ClinVar as Benign. ClinVar VariationId is 361506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.472 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BLK	NM_001715.3	c.*428G>A		3_prime_UTR_variant	Exon 13 of 13	ENST00000259089.9	NP_001706.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BLK	ENST00000259089.9	c.*428G>A		3_prime_UTR_variant	Exon 13 of 13	1	NM_001715.3	ENSP00000259089.4

Frequencies

GnomAD3 genomes AF: 0.345 AC: 52492 AN: 152148 Hom.: 10732 Cov.: 36

Gnomad AFR AF: 0.169

Gnomad AMI AF: 0.329

Gnomad AMR AF: 0.308

Gnomad ASJ AF: 0.515

Gnomad EAS AF: 0.0237

Gnomad SAS AF: 0.265

Gnomad FIN AF: 0.372

Gnomad MID AF: 0.459

Gnomad NFE AF: 0.477

Gnomad OTH AF: 0.364

GnomAD2 exomes AF: 0.345 AC: 44280 AN: 128162 AF XY: 0.350

Gnomad AFR exome AF: 0.160

Gnomad AMR exome AF: 0.248

Gnomad ASJ exome AF: 0.523

Gnomad EAS exome AF: 0.0276

Gnomad FIN exome AF: 0.407

Gnomad NFE exome AF: 0.477

Gnomad OTH exome AF: 0.417

GnomAD4 exome AF: 0.395 AC: 128455 AN: 325552 Hom.: 28084 Cov.: 0 AF XY: 0.389 AC XY: 71152 AN XY: 183118

African (AFR) AF: 0.176 AC: 1683 AN: 9552

American (AMR) AF: 0.247 AC: 6849 AN: 27726

Ashkenazi Jewish (ASJ) AF: 0.515 AC: 6083 AN: 11804

East Asian (EAS) AF: 0.0307 AC: 342 AN: 11130

South Asian (SAS) AF: 0.275 AC: 16387 AN: 59574

European-Finnish (FIN) AF: 0.407 AC: 5534 AN: 13604

Middle Eastern (MID) AF: 0.462 AC: 1361 AN: 2944

European-Non Finnish (NFE) AF: 0.483 AC: 83814 AN: 173428

Other (OTH) AF: 0.405 AC: 6402 AN: 15790

GnomAD4 genome AF: 0.345 AC: 52496 AN: 152266 Hom.: 10731 Cov.: 36 AF XY: 0.335 AC XY: 24950 AN XY: 74456

African (AFR) AF: 0.169 AC: 7034 AN: 41564

American (AMR) AF: 0.308 AC: 4711 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.515 AC: 1787 AN: 3472

East Asian (EAS) AF: 0.0235 AC: 122 AN: 5186

South Asian (SAS) AF: 0.267 AC: 1288 AN: 4830

European-Finnish (FIN) AF: 0.372 AC: 3943 AN: 10602

Middle Eastern (MID) AF: 0.456 AC: 134 AN: 294

European-Non Finnish (NFE) AF: 0.477 AC: 32415 AN: 67986

Other (OTH) AF: 0.360 AC: 762 AN: 2114

Alfa AF: 0.434 Hom.: 2716

Bravo AF: 0.328

Asia WGS AF: 0.154 AC: 539 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

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

- -

May 10, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Systemic lupus erythematosus Benign:1

-

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

BLK gene is associated with Systemic lupus erythematosus, sjogren's syndrome and other systemic inflammatory conditions. However no sufficient evidence is found to ascertain the role of this particular variant rs1042701, yet. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	8.2
DANN	Benign	0.84
PhyloP100		-0.095
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: rs1042701; hg19: chr8-11422045;