rs3192177

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001079.4(ZAP70):c.1677G>A(p.Glu559Glu) 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:7O:1

Conservation

PhyloP100: -0.295

Publications

23 publications found

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 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)

ZAP70 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 137941.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
ZAP70	NM_001079.4 link	c.1677G>A	p.Glu559Glu	synonymous_variant	Exon 13 of 14	ENST00000264972.10	NP_001070.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZAP70	ENST00000264972.10 link	c.1677G>A	p.Glu559Glu	synonymous_variant	Exon 13 of 14	1	NM_001079.4	ENSP00000264972.5

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

GnomAD2 exomes

AF:

0.273

AC:

67253

AN:

246492

AF XY:

0.273

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 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

African (AFR)

AF:

0.114

AC:

3817

AN:

33462

American (AMR)

AF:

0.193

AC:

8532

AN:

44258

Ashkenazi Jewish (ASJ)

AF:

0.204

AC:

5336

AN:

26102

East Asian (EAS)

AF:

0.00550

AC:

218

AN:

39650

South Asian (SAS)

AF:

0.139

AC:

11992

AN:

86042

European-Finnish (FIN)

AF:

0.520

AC:

27675

AN:

53264

Middle Eastern (MID)

AF:

0.164

AC:

945

AN:

5760

European-Non Finnish (NFE)

AF:

0.361

AC:

401196

AN:

1110790

Other (OTH)

AF:

0.280

AC:

16905

AN:

60282

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

20395

40790

61184

81579

101974

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12366

24732

37098

49464

61830

<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:

0.268

AC:

40741

AN:

152028

Hom.:

6889

Cov.:

AF XY:

0.272

AC XY:

20211

AN XY:

74314

show subpopulations

African (AFR)

AF:

0.123

AC:

5093

AN:

41458

American (AMR)

AF:

0.231

AC:

3534

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.186

AC:

645

AN:

3468

East Asian (EAS)

AF:

0.00771

AC:

AN:

5188

South Asian (SAS)

AF:

0.125

AC:

602

AN:

4824

European-Finnish (FIN)

AF:

0.537

AC:

5681

AN:

10582

Middle Eastern (MID)

AF:

0.204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.357

AC:

24224

AN:

67920

Other (OTH)

AF:

0.225

AC:

473

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1408

2815

4223

5630

7038

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

402

804

1206

1608

2010

<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:

0.316

Hom.:

8346

Bravo

AF:

0.239

Asia WGS

AF:

0.0840

AC:

293

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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. -

Jun 11, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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 39% of patients studied by a panel of primary immunodeficiencies. Number of patients: 37. Only high quality variants are reported. -

not provided

Benign:1Other:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

GenomeConnect, ClinGen

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

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. -

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

- -

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

-0.54

CADD

Benign

7.5

(source)

DANN

Benign

0.61

PhyloP100

-0.29

Mutation Taster

=100/0

polymorphism (auto)

(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

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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