rs55758736

chr8-11548067-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:13
• Conservation: PhyloP100: 0.860

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]

ACMG classification

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. This position pass quality control queck.
• BS2: High AC in GnomAd at 2181 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BLK	NM_001715.3	c.211G>A	p.Ala71Thr	missense_variant	4/13	ENST00000259089.9

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0143 AC: 2181 AN: 152082 Hom.: 21 Cov.: 32

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.: 25 AF XY: 0.0111 AC XY: 1513 AN XY: 135910

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.: 31 AF XY: 0.0112 AC XY: 8150 AN XY: 727172

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.: 21 Cov.: 32 AF XY: 0.0142 AC XY: 1055 AN XY: 74420

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.: 27

Bravo AF: 0.0156

TwinsUK AF: 0.00890 AC: 33

ALSPAC AF: 0.0119 AC: 46

ESP6500AA AF: 0.0216 AC: 95

ESP6500EA AF: 0.0121 AC: 104

ExAC AF: 0.0117 AC: 1421

Asia WGS AF: 0.00664 AC: 24 AN: 3478

EpiCase AF: 0.0154

EpiControl AF: 0.0162

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Maturity-onset diabetes of the young type 11 Pathogenic:1 Benign:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 25, 2009	- -
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	- -

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
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, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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:3

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) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	BLK: BP4, BS1, BS2 -

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	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	18
Dann	Benign	0.96
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.22	N
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.042	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	1.9e-8	A;A
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.16
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.56	P
Vest4		0.096
MPC		0.039
ClinPred		0.013	T
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

Other links and lift over

dbSNP: rs55758736; hg19: chr8-11405576; COSMIC: COSV52050265; COSMIC: COSV52050265;