dbSNP rs6712517: ZAP70:c.-21-115A>C (chr2-97723901-A-C) – ACMG Classification: Benign (-20 pts)

Variant summary

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

The NM_001079.4(ZAP70):c.-21-115A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.727 in 1,185,398 control chromosomes in the GnomAD database, including 321,744 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.77 ( 46342 hom., cov: 35)

Exomes 𝑓: 0.72 ( 275402 hom. )

Consequence

ZAP70
NM_001079.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -1.58

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.95).

BP6

Variant 2-97723901-A-C is Benign according to our data. Variant chr2-97723901-A-C is described in ClinVar as [Benign]. Clinvar id is 1229846.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.909 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZAP70	NM_001079.4 link	c.-21-115A>C		intron_variant	Intron 2 of 13	ENST00000264972.10	NP_001070.2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
ZAP70	ENST00000264972.10 link	c.-21-115A>C	intron_variant	Intron 2 of 13	1	NM_001079.4	ENSP00000264972.5	P43403-1
ZAP70	ENST00000698508.1 link	c.-21-115A>C	intron_variant	Intron 1 of 12			ENSP00000513759.1	P43403-1
ZAP70	ENST00000698509.1 link	n.5A>C	non_coding_transcript_exon_variant	Exon 1 of 12
ZAP70	ENST00000483781.5 link	n.173-115A>C	intron_variant	Intron 2 of 6	2

Frequencies

GnomAD3 genomes

AF:

0.770

AC:

117112

AN:

152150

Hom.:

46288

Cov.:

show subpopulations

Gnomad AFR

AF:

0.916

Gnomad AMI

AF:

0.921

Gnomad AMR

AF:

0.695

Gnomad ASJ

AF:

0.681

Gnomad EAS

AF:

0.499

Gnomad SAS

AF:

0.342

Gnomad FIN

AF:

0.749

Gnomad MID

AF:

0.778

Gnomad NFE

AF:

0.754

Gnomad OTH

AF:

0.774

GnomAD4 exome

AF:

0.721

AC:

744432

AN:

1033130

Hom.:

275402

AF XY:

0.708

AC XY:

364073

AN XY:

513866

show subpopulations

Gnomad4 AFR exome

AF:

0.925

Gnomad4 AMR exome

AF:

0.658

Gnomad4 ASJ exome

AF:

0.669

Gnomad4 EAS exome

AF:

0.481

Gnomad4 SAS exome

AF:

0.358

Gnomad4 FIN exome

AF:

0.756

Gnomad4 NFE exome

AF:

0.757

Gnomad4 OTH exome

AF:

0.706

GnomAD4 genome

AF:

0.770

AC:

117217

AN:

152268

Hom.:

46342

Cov.:

AF XY:

0.762

AC XY:

56695

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.916

Gnomad4 AMR

AF:

0.695

Gnomad4 ASJ

AF:

0.681

Gnomad4 EAS

AF:

0.499

Gnomad4 SAS

AF:

0.341

Gnomad4 FIN

AF:

0.749

Gnomad4 NFE

AF:

0.754

Gnomad4 OTH

AF:

0.767

Alfa

AF:

0.760

Hom.:

42762

Bravo

AF:

0.783

Asia WGS

AF:

0.456

AC:

1586

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

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 71% of patients studied by a panel of primary immunodeficiencies. Number of patients: 68. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.95

CADD

Benign

0.68

DANN

Benign

0.59

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