2-97723901-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.58

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]

ACMG classification

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/exons	MANE	UniProt
ZAP70	NM_001079.4	c.-21-115A>C		intron_variant		ENST00000264972.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZAP70	ENST00000264972.10	c.-21-115A>C		intron_variant		1	NM_001079.4	P1
ZAP70	ENST00000698508.1	c.-21-115A>C		intron_variant				P1
ZAP70	ENST00000698509.1	n.5A>C		non_coding_transcript_exon_variant	1/12
ZAP70	ENST00000483781.5	n.173-115A>C		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.770 AC: 117112 AN: 152150 Hom.: 46288 Cov.: 35

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

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.: 35 AF XY: 0.762 AC XY: 56695 AN XY: 74438

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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

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

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 23, 2018

- -

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

Other links and lift over

dbSNP: rs6712517; hg19: chr2-98340364;