rs145058498

Variant names:

• chr8-11550274-G-A
• rs145058498
• NM_001715.3:c.472+12G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001715.3(BLK):​c.472+12G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00141 in 1,612,548 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0061 (11 hom., cov: 33)
  • Exomes 𝑓: 0.00091 (8 hom.)
• Consequence: BLK NM_001715.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.39
• Publications: 1 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=-0.81).
• BP6: Variant 8-11550274-G-A is Benign according to our data. Variant chr8-11550274-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 258178.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00611 (931/152342) while in subpopulation AFR AF = 0.0202 (841/41578). AF 95% confidence interval is 0.0191. There are 11 homozygotes in GnomAd4. There are 438 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 931 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001715.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BLK	NM_001715.3	MANE Select	c.472+12G>A		intron	N/A	NP_001706.2
	BLK	NM_001330465.2		c.259+12G>A		intron	N/A	NP_001317394.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BLK	ENST00000259089.9	TSL:1 MANE Select	c.472+12G>A		intron	N/A	ENSP00000259089.4	P51451
	BLK	ENST00000855155.1		c.472+12G>A		intron	N/A	ENSP00000525214.1
	BLK	ENST00000855156.1		c.472+12G>A		intron	N/A	ENSP00000525215.1

Frequencies

GnomAD3 genomes AF: 0.00606 AC: 923 AN: 152224 Hom.: 11 Cov.: 33

Gnomad AFR AF: 0.0201

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00353

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00183 AC: 460 AN: 250932 AF XY: 0.00149

Gnomad AFR exome AF: 0.0215

Gnomad AMR exome AF: 0.00171

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000388

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000914 AC: 1335 AN: 1460206 Hom.: 8 Cov.: 31 AF XY: 0.000830 AC XY: 603 AN XY: 726430

African (AFR) AF: 0.0221 AC: 739 AN: 33428

American (AMR) AF: 0.00210 AC: 94 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86198

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53344

Middle Eastern (MID) AF: 0.00281 AC: 15 AN: 5346

European-Non Finnish (NFE) AF: 0.000329 AC: 365 AN: 1111072

Other (OTH) AF: 0.00196 AC: 118 AN: 60302

GnomAD4 genome AF: 0.00611 AC: 931 AN: 152342 Hom.: 11 Cov.: 33 AF XY: 0.00588 AC XY: 438 AN XY: 74498

African (AFR) AF: 0.0202 AC: 841 AN: 41578

American (AMR) AF: 0.00353 AC: 54 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000397 AC: 27 AN: 68040

Other (OTH) AF: 0.00426 AC: 9 AN: 2114

Alfa AF: 0.00334 Hom.: 2

Bravo AF: 0.00694

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Maturity-onset diabetes of the young type 11 (2)
-	-	1	not specified (1)
-	-	1	Systemic lupus erythematosus (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.23
DANN	Benign	0.68
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs145058498;

hg19: chr8-11407783;