rs55997284

chr2-97737650-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS1

The NM_001079.4(ZAP70):c.1467C>T(p.Asp489=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00141 in 1,614,082 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00096 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (5 hom.)
• Consequence: ZAP70 NM_001079.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -3.08

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 2-97737650-C-T is Benign according to our data. Variant chr2-97737650-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 389802.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1, Likely_benign=1}. Variant chr2-97737650-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-3.08 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000959 (146/152292) while in subpopulation NFE AF= 0.00157 (107/68016). AF 95% confidence interval is 0.00133. There are 0 homozygotes in gnomad4. There are 67 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZAP70	NM_001079.4	c.1467C>T	p.Asp489=	synonymous_variant	11/14	ENST00000264972.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZAP70	ENST00000264972.10	c.1467C>T	p.Asp489=	synonymous_variant	11/14	1	NM_001079.4	P1

Frequencies

GnomAD3 genomes AF: 0.000953 AC: 145 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000769

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00156

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000820 AC: 206 AN: 251188 Hom.: 1 AF XY: 0.000832 AC XY: 113 AN XY: 135782

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000817

Gnomad FIN exome AF: 0.000232

Gnomad NFE exome AF: 0.00138

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.00146 AC: 2130 AN: 1461790 Hom.: 5 Cov.: 31 AF XY: 0.00141 AC XY: 1025 AN XY: 727200

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.000378

Gnomad4 SAS exome AF: 0.000777

Gnomad4 FIN exome AF: 0.000525

Gnomad4 NFE exome AF: 0.00171

Gnomad4 OTH exome AF: 0.00146

GnomAD4 genome AF: 0.000959 AC: 146 AN: 152292 Hom.: 0 Cov.: 32 AF XY: 0.000900 AC XY: 67 AN XY: 74466

Gnomad4 AFR AF: 0.000481

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000770

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00157

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00110 Hom.: 0

Bravo AF: 0.000884

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Combined immunodeficiency due to ZAP70 deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 03, 2016

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 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
Cadd	Benign	0.59
Dann	Benign	0.35

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: rs55997284; hg19: chr2-98354113; COSMIC: COSV99385789; COSMIC: COSV99385789;