rs17488834

Variant names:

• chr2-97737676-G-T
• rs17488834
• NM_001079.4:c.1482+11G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.854
• Publications: 9 publications found

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 Gene-Disease associations (from GenCC):

• combined immunodeficiency due to ZAP70 deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 137940.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
ZAP70	NM_001079.4	c.1482+11G>T		intron_variant	Intron 11 of 13	ENST00000264972.10	NP_001070.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZAP70	ENST00000264972.10	c.1482+11G>T		intron_variant	Intron 11 of 13	1	NM_001079.4	ENSP00000264972.5

Frequencies

GnomAD3 genomes AF: 0.263 AC: 40054 AN: 152008 Hom.: 7086 Cov.: 33

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

GnomAD2 exomes AF: 0.305 AC: 76478 AN: 250920 AF XY: 0.298

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 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.: 57 AF XY: 0.327 AC XY: 237871 AN XY: 727130

African (AFR) AF: 0.0519 AC: 1739 AN: 33480

American (AMR) AF: 0.375 AC: 16757 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.206 AC: 5396 AN: 26134

East Asian (EAS) AF: 0.0983 AC: 3903 AN: 39698

South Asian (SAS) AF: 0.141 AC: 12134 AN: 86256

European-Finnish (FIN) AF: 0.525 AC: 28010 AN: 53312

Middle Eastern (MID) AF: 0.162 AC: 935 AN: 5768

European-Non Finnish (NFE) AF: 0.361 AC: 401455 AN: 1111946

Other (OTH) AF: 0.290 AC: 17503 AN: 60392

GnomAD4 genome AF: 0.263 AC: 40064 AN: 152126 Hom.: 7094 Cov.: 33 AF XY: 0.269 AC XY: 20023 AN XY: 74384

African (AFR) AF: 0.0630 AC: 2617 AN: 41526

American (AMR) AF: 0.308 AC: 4702 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.189 AC: 655 AN: 3468

East Asian (EAS) AF: 0.110 AC: 573 AN: 5188

South Asian (SAS) AF: 0.128 AC: 616 AN: 4824

European-Finnish (FIN) AF: 0.542 AC: 5729 AN: 10576

Middle Eastern (MID) AF: 0.194 AC: 57 AN: 294

European-Non Finnish (NFE) AF: 0.357 AC: 24232 AN: 67954

Other (OTH) AF: 0.234 AC: 494 AN: 2108

Alfa AF: 0.284 Hom.: 3376

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

Submissions by phenotype

not specified Benign:3

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

Jan 07, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Combined immunodeficiency due to ZAP70 deficiency Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.0060
DANN	Benign	0.38
PhyloP100		-0.85
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs17488834; hg19: chr2-98354139; COSMIC: COSV53853255; COSMIC: COSV53853255;