8-11494547-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001715.3(BLK):c.-46A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.821 in 152,266 control chromosomes in the GnomAD database, including 51,518 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.82 (51503 hom., cov: 33)
  • Exomes 𝑓: 0.81 (15 hom.)
• Consequence: BLK NM_001715.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.00

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 (BayesDel_noAF=-0.87).
• BP6: Variant 8-11494547-A-G is Benign according to our data. Variant chr8-11494547-A-G is described in ClinVar as [Benign]. Clinvar id is 361471.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.851 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BLK	NM_001715.3	c.-46A>G		5_prime_UTR_variant	1/13	ENST00000259089.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BLK	ENST00000259089.9	c.-46A>G		5_prime_UTR_variant	1/13	1	NM_001715.3	P1
BLK	ENST00000525389.1	n.379A>G		non_coding_transcript_exon_variant	1/2	1
BLK	ENST00000645242.1	n.274+7380A>G		intron_variant, non_coding_transcript_variant
BLK	ENST00000696154.2	n.274+7380A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.821 AC: 124904 AN: 152108 Hom.: 51462 Cov.: 33

Gnomad AFR AF: 0.827

Gnomad AMI AF: 0.674

Gnomad AMR AF: 0.863

Gnomad ASJ AF: 0.830

Gnomad EAS AF: 0.736

Gnomad SAS AF: 0.796

Gnomad FIN AF: 0.698

Gnomad MID AF: 0.842

Gnomad NFE AF: 0.837

Gnomad OTH AF: 0.814

GnomAD4 exome AF: 0.810 AC: 34 AN: 42 Hom.: 15 Cov.: 0 AF XY: 0.861 AC XY: 31 AN XY: 36

Gnomad4 NFE exome AF: 0.824

Gnomad4 OTH exome AF: 0.750

GnomAD4 genome AF: 0.821 AC: 125002 AN: 152224 Hom.: 51503 Cov.: 33 AF XY: 0.815 AC XY: 60632 AN XY: 74420

Gnomad4 AFR AF: 0.827

Gnomad4 AMR AF: 0.863

Gnomad4 ASJ AF: 0.830

Gnomad4 EAS AF: 0.736

Gnomad4 SAS AF: 0.796

Gnomad4 FIN AF: 0.698

Gnomad4 NFE AF: 0.837

Gnomad4 OTH AF: 0.817

Alfa AF: 0.843 Hom.: 20559

Bravo AF: 0.834

Asia WGS AF: 0.795 AC: 2765 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

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 provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	4.2
Dann	Benign	0.46

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: rs2250788; hg19: chr8-11352056;