rs17488834

Positions:

chr2-97737676-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001079.4(ZAP70):c.1482+11G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.327 in 1,613,806 control chromosomes in the GnomAD database, including 94,952 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.26 ( 7094 hom., cov: 33)

Exomes 𝑓: 0.33 ( 87858 hom. )

Consequence

ZAP70
NM_001079.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.854

Variant links:

Genes affected

ZAP70 (HGNC:12858): (zeta chain of T cell receptor associated protein kinase 70) This gene encodes an enzyme belonging to the protein tyrosine kinase family, and it plays a role in T-cell development and lymphocyte activation. This enzyme, which is phosphorylated on tyrosine residues upon T-cell antigen receptor (TCR) stimulation, functions in the initial step of TCR-mediated signal transduction in combination with the Src family kinases, Lck and Fyn. This enzyme is also essential for thymocyte development. Mutations in this gene cause selective T-cell defect, a severe combined immunodeficiency disease characterized by a selective absence of CD8-positive T-cells. Two transcript variants that encode different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ZAP70 links:

ZAP70 (HGNC:):

ZAP70 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 (BayesDel_noAF=-0.84).

BP6

Variant 2-97737676-G-T is Benign according to our data. Variant chr2-97737676-G-T is described in ClinVar as [Benign]. Clinvar id is 137940.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-97737676-G-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.353 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZAP70	NM_001079.4 linkuse as main transcript	c.1482+11G>T		intron_variant		ENST00000264972.10	NP_001070.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZAP70	ENST00000264972.10 linkuse as main transcript	c.1482+11G>T		intron_variant		1	NM_001079.4	ENSP00000264972.5		P43403-1

Frequencies

GnomAD3 genomes

AF:

0.263

AC:

40054

AN:

152008

Hom.:

7086

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0632

Gnomad AMI

AF:

0.427

Gnomad AMR

AF:

0.307

Gnomad ASJ

AF:

0.189

Gnomad EAS

AF:

0.111

Gnomad SAS

AF:

0.128

Gnomad FIN

AF:

0.542

Gnomad MID

AF:

0.190

Gnomad NFE

AF:

0.357

Gnomad OTH

AF:

0.237

GnomAD3 exomes

AF:

0.305

AC:

76478

AN:

250920

Hom.:

14017

AF XY:

0.298

AC XY:

40414

AN XY:

135648

show subpopulations

Gnomad AFR exome

AF:

0.0571

Gnomad AMR exome

AF:

0.384

Gnomad ASJ exome

AF:

0.202

Gnomad EAS exome

AF:

0.119

Gnomad SAS exome

AF:

0.138

Gnomad FIN exome

AF:

0.531

Gnomad NFE exome

AF:

0.358

Gnomad OTH exome

AF:

0.299

GnomAD4 exome

AF:

0.334

AC:

487832

AN:

1461680

Hom.:

87858

Cov.:

AF XY:

0.327

AC XY:

237871

AN XY:

727130

show subpopulations

Gnomad4 AFR exome

AF:

0.0519

Gnomad4 AMR exome

AF:

0.375

Gnomad4 ASJ exome

AF:

0.206

Gnomad4 EAS exome

AF:

0.0983

Gnomad4 SAS exome

AF:

0.141

Gnomad4 FIN exome

AF:

0.525

Gnomad4 NFE exome

AF:

0.361

Gnomad4 OTH exome

AF:

0.290

GnomAD4 genome

AF:

0.263

AC:

40064

AN:

152126

Hom.:

7094

Cov.:

AF XY:

0.269

AC XY:

20023

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.0630

Gnomad4 AMR

AF:

0.308

Gnomad4 ASJ

AF:

0.189

Gnomad4 EAS

AF:

0.110

Gnomad4 SAS

AF:

0.128

Gnomad4 FIN

AF:

0.542

Gnomad4 NFE

AF:

0.357

Gnomad4 OTH

AF:

0.234

Alfa

AF:

0.289

Hom.:

2279

Bravo

AF:

0.243

Asia WGS

AF:

0.133

AC:

460

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 07, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Nov 12, 2023	This variant is classified as Benign based on local population frequency. This variant was detected in 54% of patients studied by a panel of primary immunodeficiencies. Number of patients: 52. Only high quality variants are reported. -

ZAP70-Related Severe Combined Immunodeficiency

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Combined immunodeficiency due to ZAP70 deficiency

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.0060

DANN

Benign

0.38

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