10-96191993-A-T

Position:

chr10-96191993-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_013314.4(BLNK):c.1351T>A(p.Tyr451Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,656 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

BLNK
NM_013314.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.87

Variant links:

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 links:

ZNF518A (HGNC:29009): (zinc finger protein 518A) The protein encoded by this gene is a member of the krueppel C2H2-type zinc finger protein family. The encoded protein contains five zinc fingers and is likely a nuclear transcriptional regulator. Numerous transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Aug 2016]

ZNF518A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BLNK	NM_013314.4 linkuse as main transcript	c.1351T>A	p.Tyr451Asn	missense_variant	17/17	ENST00000224337.10	NP_037446.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BLNK	ENST00000224337.10 linkuse as main transcript	c.1351T>A	p.Tyr451Asn	missense_variant	17/17	1	NM_013314.4	ENSP00000224337	P2	Q8WV28-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251402

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135872

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461482

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727052

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Agammaglobulinemia 4, autosomal recessive

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 13, 2023

This sequence change replaces tyrosine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 451 of the BLNK protein (p.Tyr451Asn). This variant is present in population databases (rs782547336, gnomAD 0.003%). 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: 1913756). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BLNK protein function. 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

Uncertain

0.45

BayesDel_addAF

Uncertain

0.030

BayesDel_noAF

Benign

-0.11

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.88

D;.;T;.

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.96

D;D;D;D

M_CAP

Benign

0.015

MetaRNN

Uncertain

0.68

D;D;D;D

MetaSVM

Benign

-0.52

MutationAssessor

Uncertain

2.6

M;.;.;.

MutationTaster

Benign

0.99

D;D;D;D

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-5.2

D;D;.;D

REVEL

Uncertain

0.47

Sift

Benign

0.037

D;D;.;D

Sift4G

Uncertain

0.050

T;D;D;D

Polyphen

0.99

D;D;D;.

Vest4

0.62

MutPred

0.56

Gain of disorder (P = 0.0209);.;.;.;

MVP

0.76

MPC

1.4

ClinPred

0.95

GERP RS

5.3

Varity_R

0.26

gMVP

0.58

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over