rs55758736

Positions:

chr8-11548067-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001715.3(BLK):c.211G>A(p.Ala71Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0114 in 1,613,932 control chromosomes in the GnomAD database, including 156 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.014 ( 21 hom., cov: 32)

Exomes 𝑓: 0.011 ( 135 hom. )

Consequence

BLK
NM_001715.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:14

Conservation

PhyloP100: 0.860

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.042304844).

BP6

Variant 8-11548067-G-A is Benign according to our data. Variant chr8-11548067-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 12319.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-11548067-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0143 (2182/152200) while in subpopulation AFR AF= 0.0234 (971/41520). AF 95% confidence interval is 0.0222. There are 21 homozygotes in gnomad4. There are 1055 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2182 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BLK	NM_001715.3 linkuse as main transcript	c.211G>A	p.Ala71Thr	missense_variant	4/13	ENST00000259089.9	NP_001706.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
BLK	ENST00000259089.9 linkuse as main transcript	c.211G>A	p.Ala71Thr	missense_variant	4/13	1	NM_001715.3	ENSP00000259089	P1
BLK	ENST00000533828.1 linkuse as main transcript	n.409G>A		non_coding_transcript_exon_variant	2/3	4
BLK	ENST00000645242.1 linkuse as main transcript	n.362G>A		non_coding_transcript_exon_variant	3/12
BLK	ENST00000696154.2 linkuse as main transcript	n.362G>A		non_coding_transcript_exon_variant	3/12

Frequencies

GnomAD3 genomes

AF:

0.0143

AC:

2181

AN:

152082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0234

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0138

Gnomad ASJ

AF:

0.0386

Gnomad EAS

AF:

0.000770

Gnomad SAS

AF:

0.00477

Gnomad FIN

AF:

0.00142

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0114

Gnomad OTH

AF:

0.0177

GnomAD3 exomes

AF:

0.0116

AC:

2907

AN:

251454

Hom.:

AF XY:

0.0111

AC XY:

1513

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.0242

Gnomad AMR exome

AF:

0.00978

Gnomad ASJ exome

AF:

0.0405

Gnomad EAS exome

AF:

0.000217

Gnomad SAS exome

AF:

0.00686

Gnomad FIN exome

AF:

0.00222

Gnomad NFE exome

AF:

0.0123

Gnomad OTH exome

AF:

0.0176

GnomAD4 exome

AF:

0.0111

AC:

16258

AN:

1461732

Hom.:

135

Cov.:

AF XY:

0.0112

AC XY:

8150

AN XY:

727172

show subpopulations

Gnomad4 AFR exome

AF:

0.0266

Gnomad4 AMR exome

AF:

0.00984

Gnomad4 ASJ exome

AF:

0.0393

Gnomad4 EAS exome

AF:

0.000176

Gnomad4 SAS exome

AF:

0.00682

Gnomad4 FIN exome

AF:

0.00236

Gnomad4 NFE exome

AF:

0.0108

Gnomad4 OTH exome

AF:

0.0141

GnomAD4 genome

AF:

0.0143

AC:

2182

AN:

152200

Hom.:

Cov.:

AF XY:

0.0142

AC XY:

1055

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.0234

Gnomad4 AMR

AF:

0.0137

Gnomad4 ASJ

AF:

0.0386

Gnomad4 EAS

AF:

0.000772

Gnomad4 SAS

AF:

0.00436

Gnomad4 FIN

AF:

0.00142

Gnomad4 NFE

AF:

0.0114

Gnomad4 OTH

AF:

0.0175

Alfa

AF:

0.0136

Hom.:

Bravo

AF:

0.0156

TwinsUK

AF:

0.00890

AC:

ALSPAC

AF:

0.0119

AC:

ESP6500AA

AF:

0.0216

AC:

ESP6500EA

AF:

0.0121

AC:

104

ExAC

AF:

0.0117

AC:

1421

Asia WGS

AF:

0.00664

AC:

AN:

3478

EpiCase

AF:

0.0154

EpiControl

AF:

0.0162

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Maturity-onset diabetes of the young type 11

Pathogenic:1Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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. -
Benign, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Mar 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 05, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 25, 2009	- -

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 23, 2013	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided

Benign:4

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	BLK: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 25, 2018	This variant is associated with the following publications: (PMID: 22696686, 20981092, 26821283, 23261300, 22995991, 25333069, 19667185, 23224494, 27884173, 31101814, 32028929) -

Monogenic diabetes

Benign:1

Benign, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Mar 03, 2017

ACMG Criteria:BP4 (6 predictors), PP3 (4 predictors), BS1 (2.5% in African 1.6% in European in 1000g), BS2 (about equal cases and controls in type2diabetesgenetics.org), PS3 (functional studies show effect) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.21

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.22

LIST_S2

Uncertain

0.89

MetaRNN

Benign

0.042

MetaSVM

Benign

-0.79

MutationAssessor

Uncertain

2.5

MutationTaster

Benign

1.9e-8

A;A

PrimateAI

Benign

0.32

PROVEAN

Benign

-2.1

REVEL

Benign

0.16

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.0060

Polyphen

0.56

Vest4

0.096

MPC

0.039

ClinPred

0.013

GERP RS

3.4

Varity_R

0.079

gMVP

0.34

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over