Genetic Variant ZAP70:c.-101+81A>G (chr2-97713755-A-G) – 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.-101+81A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.683 in 152,352 control chromosomes in the GnomAD database, including 36,551 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.68 ( 36474 hom., cov: 32)

Exomes 𝑓: 0.71 ( 77 hom. )

Consequence

ZAP70
NM_001079.4 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.100

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=-0.91).

BP6

Variant 2-97713755-A-G is Benign according to our data. Variant chr2-97713755-A-G is described in ClinVar as [Benign]. Clinvar id is 1226084.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.729 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZAP70	NM_001079.4 link	c.-101+81A>G		intron_variant	Intron 1 of 13	ENST00000264972.10	NP_001070.2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
ZAP70	ENST00000264972.10 link	c.-101+81A>G	intron_variant	Intron 1 of 13	1	NM_001079.4	ENSP00000264972.5	P43403-1
ZAP70	ENST00000483781.5 link	n.93+81A>G	intron_variant	Intron 1 of 6	2
ZAP70	ENST00000698508.1 link	c.-261A>G	upstream_gene_variant				ENSP00000513759.1	P43403-1

Frequencies

GnomAD3 genomes

AF:

0.684

AC:

103868

AN:

151948

Hom.:

36455

Cov.:

show subpopulations

Gnomad AFR

AF:

0.703

Gnomad AMI

AF:

0.813

Gnomad AMR

AF:

0.578

Gnomad ASJ

AF:

0.621

Gnomad EAS

AF:

0.386

Gnomad SAS

AF:

0.272

Gnomad FIN

AF:

0.773

Gnomad MID

AF:

0.684

Gnomad NFE

AF:

0.735

Gnomad OTH

AF:

0.687

GnomAD4 exome

AF:

0.711

AC:

202

AN:

284

Hom.:

Cov.:

AF XY:

0.733

AC XY:

151

AN XY:

206

show subpopulations

Gnomad4 AFR exome

AF:

1.00

Gnomad4 AMR exome

AF:

0.333

Gnomad4 ASJ exome

AF:

1.00

Gnomad4 EAS exome

AF:

0.333

Gnomad4 SAS exome

AF:

0.300

Gnomad4 FIN exome

AF:

0.750

Gnomad4 NFE exome

AF:

0.757

Gnomad4 OTH exome

AF:

0.643

GnomAD4 genome

AF:

0.683

AC:

103928

AN:

152068

Hom.:

36474

Cov.:

AF XY:

0.676

AC XY:

50240

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.702

Gnomad4 AMR

AF:

0.578

Gnomad4 ASJ

AF:

0.621

Gnomad4 EAS

AF:

0.386

Gnomad4 SAS

AF:

0.272

Gnomad4 FIN

AF:

0.773

Gnomad4 NFE

AF:

0.735

Gnomad4 OTH

AF:

0.682

Alfa

AF:

0.724

Hom.:

5138

Bravo

AF:

0.675

Asia WGS

AF:

0.386

AC:

1346

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

Jun 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified

Benign:1

Jan 24, 2024

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 77% of patients studied by a panel of primary immunodeficiencies. Number of patients: 73. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

7.4

DANN

Benign

0.62

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