8-11494403-C-T

Variant names:

• chr8-11494403-C-T
• rs922483
• ENST00000525389.1:n.235C>T

Variant summary

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

The NM_001715.3(BLK):​c.-190C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.321 in 152,170 control chromosomes in the GnomAD database, including 8,898 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (8896 hom., cov: 32)
  • Exomes 𝑓: 0.28 (2 hom.)
• Consequence: BLK NM_001715.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.38
• Publications: 58 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 8-11494403-C-T is Benign according to our data. Variant chr8-11494403-C-T is described in ClinVar as [Benign]. Clinvar id is 361468.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.701 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BLK	NM_001715.3	c.-190C>T		5_prime_UTR_variant	Exon 1 of 13	ENST00000259089.9	NP_001706.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BLK	ENST00000525389.1	n.235C>T		non_coding_transcript_exon_variant	Exon 1 of 2	1
BLK	ENST00000259089.9	c.-190C>T		5_prime_UTR_variant	Exon 1 of 13	1	NM_001715.3	ENSP00000259089.4
BLK	ENST00000645242.1	n.274+7236C>T		intron_variant	Intron 1 of 11
BLK	ENST00000696154.2	n.274+7236C>T		intron_variant	Intron 1 of 11

Frequencies

GnomAD3 genomes AF: 0.321 AC: 48852 AN: 151988 Hom.: 8879 Cov.: 32

Gnomad AFR AF: 0.260

Gnomad AMI AF: 0.311

Gnomad AMR AF: 0.494

Gnomad ASJ AF: 0.232

Gnomad EAS AF: 0.719

Gnomad SAS AF: 0.419

Gnomad FIN AF: 0.304

Gnomad MID AF: 0.297

Gnomad NFE AF: 0.291

Gnomad OTH AF: 0.321

GnomAD4 exome AF: 0.281 AC: 18 AN: 64 Hom.: 2 Cov.: 0 AF XY: 0.283 AC XY: 13 AN XY: 46

African (AFR) AC: 0 AN: 0

American (AMR) AF: 0.500 AC: 1 AN: 2

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.500 AC: 1 AN: 2

Middle Eastern (MID) AF: 0.250 AC: 1 AN: 4

European-Non Finnish (NFE) AF: 0.241 AC: 13 AN: 54

Other (OTH) AF: 1.00 AC: 2 AN: 2

GnomAD4 genome AF: 0.322 AC: 48904 AN: 152106 Hom.: 8896 Cov.: 32 AF XY: 0.329 AC XY: 24465 AN XY: 74342

African (AFR) AF: 0.260 AC: 10768 AN: 41492

American (AMR) AF: 0.494 AC: 7559 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.232 AC: 807 AN: 3472

East Asian (EAS) AF: 0.720 AC: 3712 AN: 5156

South Asian (SAS) AF: 0.418 AC: 2013 AN: 4818

European-Finnish (FIN) AF: 0.304 AC: 3220 AN: 10576

Middle Eastern (MID) AF: 0.303 AC: 89 AN: 294

European-Non Finnish (NFE) AF: 0.291 AC: 19758 AN: 67978

Other (OTH) AF: 0.329 AC: 696 AN: 2114

Alfa AF: 0.319 Hom.: 9019

Bravo AF: 0.339

Asia WGS AF: 0.584 AC: 2030 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

Jan 12, 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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	10
DANN	Benign	0.79
PhyloP100		1.4
PromoterAI		0.030	Neutral
Mutation Taster		=298/2	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: rs922483; hg19: chr8-11351912;