rs11540858

Variant names:

• chr10-96247049-C-T
• rs11540858
• NM_013314.4:c.48G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_013314.4(BLNK):​c.48G>A​(p.Arg16Arg) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00686 in 1,598,140 control chromosomes in the GnomAD database, including 597 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 0.035 (307 hom., cov: 33)
  • Exomes 𝑓: 0.0039 (290 hom.)
• Consequence: BLNK NM_013314.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.002921
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.82
• Publications: 3 publications found

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]

BLNK Gene-Disease associations (from GenCC):

• agammaglobulinemia 4, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
• autosomal agammaglobulinemia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.25).
• BP6: Variant 10-96247049-C-T is Benign according to our data. Variant chr10-96247049-C-T is described in ClinVar as Benign. ClinVar VariationId is 471480.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.82 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.115 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BLNK	NM_013314.4	c.48G>A	p.Arg16Arg	splice_region_variant, synonymous_variant	Exon 2 of 17	ENST00000224337.10	NP_037446.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BLNK	ENST00000224337.10	c.48G>A	p.Arg16Arg	splice_region_variant, synonymous_variant	Exon 2 of 17	1	NM_013314.4	ENSP00000224337.6

Frequencies

GnomAD3 genomes AF: 0.0346 AC: 5256 AN: 152080 Hom.: 307 Cov.: 33

Gnomad AFR AF: 0.118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0158

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.000970

Gnomad OTH AF: 0.0287

GnomAD2 exomes AF: 0.00958 AC: 2328 AN: 243120 AF XY: 0.00723

Gnomad AFR exome AF: 0.122

Gnomad AMR exome AF: 0.00669

Gnomad ASJ exome AF: 0.000103

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000898

Gnomad OTH exome AF: 0.00559

GnomAD4 exome AF: 0.00395 AC: 5709 AN: 1445942 Hom.: 290 Cov.: 28 AF XY: 0.00354 AC XY: 2548 AN XY: 718854

African (AFR) AF: 0.117 AC: 3825 AN: 32580

American (AMR) AF: 0.00832 AC: 357 AN: 42884

Ashkenazi Jewish (ASJ) AF: 0.000155 AC: 4 AN: 25776

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39476

South Asian (SAS) AF: 0.00112 AC: 92 AN: 82216

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52686

Middle Eastern (MID) AF: 0.0137 AC: 78 AN: 5692

European-Non Finnish (NFE) AF: 0.000680 AC: 751 AN: 1104920

Other (OTH) AF: 0.0101 AC: 601 AN: 59712

GnomAD4 genome AF: 0.0346 AC: 5262 AN: 152198 Hom.: 307 Cov.: 33 AF XY: 0.0338 AC XY: 2518 AN XY: 74412

African (AFR) AF: 0.118 AC: 4881 AN: 41490

American (AMR) AF: 0.0158 AC: 242 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.000970 AC: 66 AN: 68014

Other (OTH) AF: 0.0279 AC: 59 AN: 2116

Alfa AF: 0.0129 Hom.: 188

Bravo AF: 0.0388

Asia WGS AF: 0.00924 AC: 33 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Agammaglobulinemia 4, autosomal recessive Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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	-0.25
CADD	Benign	16
DANN	Benign	0.76
PhyloP100		1.8
Mutation Taster		=71/29	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0029
dbscSNV1_RF	Benign	0.17
SpliceAI score (max)		0.11		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: rs11540858; hg19: chr10-98006805;