rs17111459

Positions:

• chr10-96216739-C-G

Variant summary

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

The NM_013314.4(BLNK):​c.526-5G>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00759 in 1,612,622 control chromosomes in the GnomAD database, including 90 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (22 hom., cov: 32)
  • Exomes 𝑓: 0.0071 (68 hom.)
• Consequence: BLNK NM_013314.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00002228
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.188

Genes affected

BLNK (HGNC:14211): (B cell linker) This gene encodes a cytoplasmic linker or adaptor protein that plays a critical role in B cell development. This protein bridges B cell receptor-associated kinase activation with downstream signaling pathways, thereby affecting various biological functions. The phosphorylation of five tyrosine residues is necessary for this protein to nucleate distinct signaling effectors following B cell receptor activation. Mutations in this gene cause hypoglobulinemia and absent B cells, a disease in which the pro- to pre-B-cell transition is developmentally blocked. Deficiency in this protein has also been shown in some cases of pre-B acute lymphoblastic leukemia. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, May 2012]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 10-96216739-C-G is Benign according to our data. Variant chr10-96216739-C-G is described in ClinVar as [Benign]. Clinvar id is 471481.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-96216739-C-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.012 (1825/152176) while in subpopulation AFR AF= 0.024 (998/41526). AF 95% confidence interval is 0.0228. There are 22 homozygotes in gnomad4. There are 868 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BLNK	NM_013314.4	c.526-5G>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000224337.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BLNK	ENST00000224337.10	c.526-5G>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_013314.4	P2

Frequencies

GnomAD3 genomes AF: 0.0120 AC: 1820 AN: 152058 Hom.: 23 Cov.: 32

Gnomad AFR AF: 0.0240

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0102

Gnomad ASJ AF: 0.00547

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00725

Gnomad FIN AF: 0.00180

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00823

Gnomad OTH AF: 0.0163

GnomAD3 exomes AF: 0.00699 AC: 1755 AN: 251020 Hom.: 18 AF XY: 0.00705 AC XY: 957 AN XY: 135670

Gnomad AFR exome AF: 0.0236

Gnomad AMR exome AF: 0.00544

Gnomad ASJ exome AF: 0.00656

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00507

Gnomad FIN exome AF: 0.00222

Gnomad NFE exome AF: 0.00759

Gnomad OTH exome AF: 0.00883

GnomAD4 exome AF: 0.00713 AC: 10410 AN: 1460446 Hom.: 68 Cov.: 29 AF XY: 0.00722 AC XY: 5247 AN XY: 726652

Gnomad4 AFR exome AF: 0.0238

Gnomad4 AMR exome AF: 0.00577

Gnomad4 ASJ exome AF: 0.00567

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00536

Gnomad4 FIN exome AF: 0.00247

Gnomad4 NFE exome AF: 0.00722

Gnomad4 OTH exome AF: 0.00816

GnomAD4 genome AF: 0.0120 AC: 1825 AN: 152176 Hom.: 22 Cov.: 32 AF XY: 0.0117 AC XY: 868 AN XY: 74388

Gnomad4 AFR AF: 0.0240

Gnomad4 AMR AF: 0.0101

Gnomad4 ASJ AF: 0.00547

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00726

Gnomad4 FIN AF: 0.00180

Gnomad4 NFE AF: 0.00823

Gnomad4 OTH AF: 0.0161

Alfa AF: 0.00847 Hom.: 0

Bravo AF: 0.0121

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Agammaglobulinemia 4, autosomal recessive Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 28, 2020	- -

BLNK-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 11, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.34
DANN	Benign	0.51

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000022
dbscSNV1_RF	Benign	0.0080
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: rs17111459; hg19: chr10-97976495;