chr2-97713589-C-A

Position:

• chr2-97713589-C-A

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.-186C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.309 in 152,222 control chromosomes in the GnomAD database, including 9,780 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (9769 hom., cov: 33)
  • Exomes 𝑓: 0.50 (11 hom.)
• Consequence: ZAP70 NM_001079.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.96

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=-0.79).
• BP6: Variant 2-97713589-C-A is Benign according to our data. Variant chr2-97713589-C-A is described in ClinVar as [Benign]. Clinvar id is 337620.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.433 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZAP70	NM_001079.4	c.-186C>A		5_prime_UTR_variant	1/14	ENST00000264972.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZAP70	ENST00000264972.10	c.-186C>A		5_prime_UTR_variant	1/14	1	NM_001079.4	P1
ZAP70	ENST00000483781.5	n.8C>A		non_coding_transcript_exon_variant	1/7	2

Frequencies

GnomAD3 genomes AF: 0.309 AC: 47055 AN: 152042 Hom.: 9768 Cov.: 33

Gnomad AFR AF: 0.0759

Gnomad AMI AF: 0.379

Gnomad AMR AF: 0.248

Gnomad ASJ AF: 0.221

Gnomad EAS AF: 0.252

Gnomad SAS AF: 0.153

Gnomad FIN AF: 0.631

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.437

Gnomad OTH AF: 0.266

GnomAD4 exome AF: 0.500 AC: 31 AN: 62 Hom.: 11 Cov.: 0 AF XY: 0.417 AC XY: 20 AN XY: 48

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.929

Gnomad4 NFE exome AF: 0.429

GnomAD4 genome AF: 0.309 AC: 47056 AN: 152160 Hom.: 9769 Cov.: 33 AF XY: 0.313 AC XY: 23258 AN XY: 74382

Gnomad4 AFR AF: 0.0757

Gnomad4 AMR AF: 0.248

Gnomad4 ASJ AF: 0.221

Gnomad4 EAS AF: 0.252

Gnomad4 SAS AF: 0.153

Gnomad4 FIN AF: 0.631

Gnomad4 NFE AF: 0.437

Gnomad4 OTH AF: 0.263

Alfa AF: 0.385 Hom.: 15064

Bravo AF: 0.273

Asia WGS AF: 0.177 AC: 615 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 30, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jan 24, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 49% of patients studied by a panel of primary immunodeficiencies. Number of patients: 47. Only high quality variants are reported. -

Combined immunodeficiency due to ZAP70 deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.3
DANN	Benign	0.66

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: rs2276645; hg19: chr2-98330052;