rs143109144

Variant names:

• chr10-96247009-C-G
• rs143109144
• NM_013314.4:c.88G>C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_Supporting

The NM_013314.4(BLNK):​c.88G>C​(p.Gly30Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000949 in 1,607,588 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00070 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00097 (0 hom.)
• Consequence: BLNK NM_013314.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 3.15

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.045404345).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000703 (107/152238) while in subpopulation NFE AF= 0.00121 (82/68012). AF 95% confidence interval is 0.000995. There are 0 homozygotes in gnomad4. There are 50 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BLNK	NM_013314.4	c.88G>C	p.Gly30Arg	missense_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.88G>C	p.Gly30Arg	missense_variant	Exon 2 of 17	1	NM_013314.4	ENSP00000224337.6

Frequencies

GnomAD3 genomes AF: 0.000703 AC: 107 AN: 152120 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000660

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00121

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000718 AC: 179 AN: 249474 Hom.: 0 AF XY: 0.000772 AC XY: 104 AN XY: 134796

Gnomad AFR exome AF: 0.000186

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000649

Gnomad NFE exome AF: 0.00125

Gnomad OTH exome AF: 0.000822

GnomAD4 exome AF: 0.000974 AC: 1418 AN: 1455350 Hom.: 0 Cov.: 29 AF XY: 0.000935 AC XY: 677 AN XY: 723830

Gnomad4 AFR exome AF: 0.0000902

Gnomad4 AMR exome AF: 0.0000225

Gnomad4 ASJ exome AF: 0.00123

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000659

Gnomad4 NFE exome AF: 0.00118

Gnomad4 OTH exome AF: 0.000598

GnomAD4 genome AF: 0.000703 AC: 107 AN: 152238 Hom.: 0 Cov.: 33 AF XY: 0.000672 AC XY: 50 AN XY: 74446

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000660

Gnomad4 NFE AF: 0.00121

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00116 Hom.: 0

Bravo AF: 0.000627

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000750 AC: 91

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Dec 19, 2019

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Agammaglobulinemia 4, autosomal recessive Uncertain:1

Jan 16, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 30 of the BLNK protein (p.Gly30Arg). This variant is present in population databases (rs143109144, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with BLNK-related conditions. ClinVar contains an entry for this variant (Variation ID: 538834). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt BLNK protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.67	D;.;T;.;T
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.95	D;D;D;D;D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.045	T;T;T;T;T
MetaSVM	Benign	-0.33	T
MutationAssessor	Uncertain	2.7	M;M;.;M;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.7	D;D;D;D;.
REVEL	Benign	0.21
Sift	Uncertain	0.0070	D;D;D;D;.
Sift4G	Uncertain	0.015	D;D;D;D;D
Polyphen		1.0	D;D;D;.;.
Vest4		0.36
MVP		0.71
MPC		1.2
ClinPred		0.13	T
GERP RS		5.7
Varity_R		0.27
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs143109144; hg19: chr10-98006765;