rs148612299

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -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. 15/20 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

Publications

7 publications found

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 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

BLNK links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 252680.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BLNK	NM_013314.4 link	c.472G>T	p.Ala158Ser	missense_variant	Exon 6 of 17	ENST00000224337.10	NP_037446.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BLNK	ENST00000224337.10 link	c.472G>T	p.Ala158Ser	missense_variant	Exon 6 of 17	1	NM_013314.4	ENSP00000224337.6

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

GnomAD2 exomes

AF:

0.00605

AC:

1521

AN:

251470

AF XY:

0.00611

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 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

African (AFR)

AF:

0.00143

AC:

AN:

33472

American (AMR)

AF:

0.00771

AC:

345

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0353

AC:

923

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00333

AC:

287

AN:

86238

European-Finnish (FIN)

AF:

0.00535

AC:

286

AN:

53414

Middle Eastern (MID)

AF:

0.0167

AC:

AN:

5580

European-Non Finnish (NFE)

AF:

0.00466

AC:

5179

AN:

1112006

Other (OTH)

AF:

0.00628

AC:

379

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

451

903

1354

1806

2257

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

198

396

594

792

990

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00494

AC:

752

AN:

152244

Hom.:

Cov.:

AF XY:

0.00518

AC XY:

386

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.00103

AC:

AN:

41550

American (AMR)

AF:

0.00628

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0381

AC:

132

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00104

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00829

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.0442

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00494

AC:

336

AN:

68012

Other (OTH)

AF:

0.00806

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

118

158

197

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00588

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

Oct 11, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 13, 2022

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Apr 19, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Jan 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BLNK: BP4, BS1, BS2 -

Mar 17, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

Sep 24, 2015

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

BLNK-related disorder

Benign:1

Aug 29, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

(source)

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

PhyloP100

-0.43

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

Mutation Taster

=98/2

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over