rs148612299

chr10-96223879-C-Achr10-96223879-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.429

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 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 GnomAd at 6 AR gene

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BLNK	ENST00000224337.10	c.472G>T	p.Ala158Ser	missense_variant	6/17	1	NM_013314.4	P2

Frequencies

GnomAD3 genomes AF: 0.00494 AC: 752 AN: 152126 Hom.: 6 Cov.: 32

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.: 15 AF XY: 0.00611 AC XY: 830 AN XY: 135914

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.: 48 Cov.: 32 AF XY: 0.00532 AC XY: 3865 AN XY: 727120

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.: 6 Cov.: 32 AF XY: 0.00518 AC XY: 386 AN XY: 74446

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.: 16

Bravo AF: 0.00526

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00767 AC: 66

ExAC AF: 0.00548 AC: 665

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00791

EpiControl AF: 0.00859

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Agammaglobulinemia 4, autosomal recessive Benign:4

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 19, 2022	- -
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. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 28, 2023	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 17, 2017	- -
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, criteria provided, single submitter

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	T
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	N
LIST_S2	Benign	0.53	T;T;T
MetaRNN	Benign	0.0030	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.59	N;N;N
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.30	T
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	T
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

Other links and lift over

dbSNP: rs148612299; hg19: chr10-97983635; COSMIC: COSV56412312;