rs56127120

chr2-97724141-G-Achr2-97724141-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001079.4(ZAP70):c.105G>A(p.Leu35=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00371 in 1,569,446 control chromosomes in the GnomAD database, including 172 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0045 (17 hom., cov: 33)
  • Exomes 𝑓: 0.0036 (155 hom.)
• Consequence: ZAP70 NM_001079.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.20

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 2-97724141-G-A is Benign according to our data. Variant chr2-97724141-G-A is described in ClinVar as [Benign]. Clinvar id is 337626.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=3.2 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0616 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZAP70	NM_001079.4	c.105G>A	p.Leu35=	synonymous_variant	3/14	ENST00000264972.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZAP70	ENST00000264972.10	c.105G>A	p.Leu35=	synonymous_variant	3/14	1	NM_001079.4	P1
ZAP70	ENST00000698508.1	c.105G>A	p.Leu35=	synonymous_variant	2/13			P1
ZAP70	ENST00000483781.5	n.298G>A		non_coding_transcript_exon_variant	3/7	2
ZAP70	ENST00000698509.1	n.245G>A		non_coding_transcript_exon_variant	1/12

Frequencies

GnomAD3 genomes AF: 0.00449 AC: 683 AN: 152254 Hom.: 17 Cov.: 33

Gnomad AFR AF: 0.00142

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000392

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0672

Gnomad SAS AF: 0.00744

Gnomad FIN AF: 0.0144

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00103

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00671 AC: 1251 AN: 186372 Hom.: 25 AF XY: 0.00611 AC XY: 627 AN XY: 102618

Gnomad AFR exome AF: 0.00147

Gnomad AMR exome AF: 0.000169

Gnomad ASJ exome AF: 0.000111

Gnomad EAS exome AF: 0.0598

Gnomad SAS exome AF: 0.00320

Gnomad FIN exome AF: 0.0146

Gnomad NFE exome AF: 0.00106

Gnomad OTH exome AF: 0.00780

GnomAD4 exome AF: 0.00363 AC: 5142 AN: 1417074 Hom.: 155 Cov.: 32 AF XY: 0.00357 AC XY: 2507 AN XY: 701430

Gnomad4 AFR exome AF: 0.000765

Gnomad4 AMR exome AF: 0.000173

Gnomad4 ASJ exome AF: 0.000118

Gnomad4 EAS exome AF: 0.0842

Gnomad4 SAS exome AF: 0.00402

Gnomad4 FIN exome AF: 0.0133

Gnomad4 NFE exome AF: 0.000614

Gnomad4 OTH exome AF: 0.00650

GnomAD4 genome AF: 0.00450 AC: 685 AN: 152372 Hom.: 17 Cov.: 33 AF XY: 0.00543 AC XY: 405 AN XY: 74518

Gnomad4 AFR AF: 0.00142

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.0674

Gnomad4 SAS AF: 0.00745

Gnomad4 FIN AF: 0.0144

Gnomad4 NFE AF: 0.00103

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00159 Hom.: 1

Bravo AF: 0.00263

Asia WGS AF: 0.0500 AC: 173 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 04, 2017

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. -

ZAP70-Related Severe Combined Immunodeficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Combined immunodeficiency due to ZAP70 deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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	-0.49
Cadd	Benign	8.5
Dann	Benign	0.77

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: rs56127120; hg19: chr2-98340604; COSMIC: COSV53858413; COSMIC: COSV53858413;