rs148612299

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_013314.4(BLNK):c.472G>T(p.Ala158Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00514 in 1,613,884 control chromosomes in the GnomAD database, including 54 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0049 ( 6 hom., cov: 32)

Exomes 𝑓: 0.0052 ( 48 hom. )

Consequence

BLNK
NM_013314.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.429

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002996534).

BP6

Variant 10-96223879-C-A is Benign according to our data. Variant chr10-96223879-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 252680.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-96223879-C-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00494 (752/152244) while in subpopulation AMR AF= 0.00628 (96/15296). AF 95% confidence interval is 0.00526. There are 6 homozygotes in gnomad4. There are 386 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BLNK	NM_013314.4 link	c.472G>T	p.Ala158Ser	missense_variant	6/17	ENST00000224337.10	NP_037446.1	Q8WV28-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BLNK	ENST00000224337.10 link	c.472G>T	p.Ala158Ser	missense_variant	6/17	1	NM_013314.4	ENSP00000224337.6		Q8WV28-1

Frequencies

GnomAD3 genomes

AF:

0.00494

AC:

752

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00104

Gnomad AMI

AF:

0.0242

Gnomad AMR

AF:

0.00628

Gnomad ASJ

AF:

0.0381

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00829

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.00494

Gnomad OTH

AF:

0.00766

GnomAD3 exomes

AF:

0.00605

AC:

1521

AN:

251470

Hom.:

AF XY:

0.00611

AC XY:

830

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.000615

Gnomad AMR exome

AF:

0.00702

Gnomad ASJ exome

AF:

0.0369

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00291

Gnomad FIN exome

AF:

0.00702

Gnomad NFE exome

AF:

0.00527

Gnomad OTH exome

AF:

0.00912

GnomAD4 exome

AF:

0.00516

AC:

7540

AN:

1461640

Hom.:

Cov.:

AF XY:

0.00532

AC XY:

3865

AN XY:

727120

show subpopulations

Gnomad4 AFR exome

AF:

0.00143

Gnomad4 AMR exome

AF:

0.00771

Gnomad4 ASJ exome

AF:

0.0353

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00333

Gnomad4 FIN exome

AF:

0.00535

Gnomad4 NFE exome

AF:

0.00466

Gnomad4 OTH exome

AF:

0.00628

GnomAD4 genome

AF:

0.00494

AC:

752

AN:

152244

Hom.:

Cov.:

AF XY:

0.00518

AC XY:

386

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.00103

Gnomad4 AMR

AF:

0.00628

Gnomad4 ASJ

AF:

0.0381

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00829

Gnomad4 NFE

AF:

0.00494

Gnomad4 OTH

AF:

0.00806

Alfa

AF:

0.00694

Hom.:

Bravo

AF:

0.00526

TwinsUK

AF:

0.00405

AC:

ALSPAC

AF:

0.00493

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00767

AC:

ExAC

AF:

0.00548

AC:

665

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00791

EpiControl

AF:

0.00859

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Agammaglobulinemia 4, autosomal recessive

Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 28, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Oct 13, 2022	This variant is present in the Genome Aggregation Database (Highest reported MAF: 3.7% [382/10370], including 17 homozygotes; https://gnomad.broadinstitute.org/variant/10-97983635-C-A?dataset=gnomad_r2_1), and in ClinVar, with multiple laboratories classifying it as a benign or likely benign (Variation ID: 252680). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, this variant is not expected to cause disease and is classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 19, 2022	- -

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 17, 2017	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	BLNK: BP4, BS1, BS2 -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Sep 24, 2015

- -

BLNK-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 29, 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

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.77

CADD

Benign

0.098

DANN

Benign

0.45

DEOGEN2

Benign

0.30

T;.;.

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.0065

LIST_S2

Benign

0.53

T;T;T

MetaRNN

Benign

0.0030

T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-0.59

N;N;N

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.71

N;N;N

REVEL

Benign

0.032

Sift

Benign

0.55

T;T;T

Sift4G

Benign

0.56

T;T;T

Polyphen

0.0

B;B;.

Vest4

0.028

MVP

0.21

MPC

0.29

ClinPred

0.0026

GERP RS

-6.9

Varity_R

0.039

gMVP

0.13

Splicing

Name

Calibrated prediction

Score

Prediction

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

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