rs3192177

Positions:

chr2-97738048-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001079.4(ZAP70):c.1677G>A(p.Glu559=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.321 in 1,611,638 control chromosomes in the GnomAD database, including 91,892 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.27 ( 6889 hom., cov: 32)

Exomes 𝑓: 0.33 ( 85003 hom. )

Consequence

ZAP70
NM_001079.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6O:1

Conservation

PhyloP100: -0.295

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.54).

BP6

Variant 2-97738048-G-A is Benign according to our data. Variant chr2-97738048-G-A is described in ClinVar as [Benign]. Clinvar id is 137941.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-97738048-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.295 with no splicing effect.

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	UniProt
ZAP70	NM_001079.4 linkuse as main transcript	c.1677G>A	p.Glu559=	synonymous_variant	13/14	ENST00000264972.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZAP70	ENST00000264972.10 linkuse as main transcript	c.1677G>A	p.Glu559=	synonymous_variant	13/14	1	NM_001079.4	P1	P43403-1

Frequencies

GnomAD3 genomes

AF:

0.268

AC:

40743

AN:

151912

Hom.:

6890

Cov.:

show subpopulations

Gnomad AFR

AF:

0.123

Gnomad AMI

AF:

0.427

Gnomad AMR

AF:

0.232

Gnomad ASJ

AF:

0.186

Gnomad EAS

AF:

0.00769

Gnomad SAS

AF:

0.125

Gnomad FIN

AF:

0.537

Gnomad MID

AF:

0.199

Gnomad NFE

AF:

0.357

Gnomad OTH

AF:

0.228

GnomAD3 exomes

AF:

0.273

AC:

67253

AN:

246492

Hom.:

11590

AF XY:

0.273

AC XY:

36432

AN XY:

133372

show subpopulations

Gnomad AFR exome

AF:

0.121

Gnomad AMR exome

AF:

0.189

Gnomad ASJ exome

AF:

0.201

Gnomad EAS exome

AF:

0.00666

Gnomad SAS exome

AF:

0.137

Gnomad FIN exome

AF:

0.528

Gnomad NFE exome

AF:

0.359

Gnomad OTH exome

AF:

0.275

GnomAD4 exome

AF:

0.327

AC:

476616

AN:

1459610

Hom.:

85003

Cov.:

AF XY:

0.321

AC XY:

232951

AN XY:

726020

show subpopulations

Gnomad4 AFR exome

AF:

0.114

Gnomad4 AMR exome

AF:

0.193

Gnomad4 ASJ exome

AF:

0.204

Gnomad4 EAS exome

AF:

0.00550

Gnomad4 SAS exome

AF:

0.139

Gnomad4 FIN exome

AF:

0.520

Gnomad4 NFE exome

AF:

0.361

Gnomad4 OTH exome

AF:

0.280

GnomAD4 genome

AF:

0.268

AC:

40741

AN:

152028

Hom.:

6889

Cov.:

AF XY:

0.272

AC XY:

20211

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.123

Gnomad4 AMR

AF:

0.231

Gnomad4 ASJ

AF:

0.186

Gnomad4 EAS

AF:

0.00771

Gnomad4 SAS

AF:

0.125

Gnomad4 FIN

AF:

0.537

Gnomad4 NFE

AF:

0.357

Gnomad4 OTH

AF:

0.225

Alfa

AF:

0.319

Hom.:

5443

Bravo

AF:

0.239

Asia WGS

AF:

0.0840

AC:

293

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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 39% of patients studied by a panel of primary immunodeficiencies. Number of patients: 37. Only high quality variants are reported. -
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	Eurofins Ntd Llc (ga)	Jun 11, 2016	- -

ZAP70-Related Severe Combined Immunodeficiency

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

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

Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.54

CADD

Benign

7.5

DANN

Benign

0.61

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