rs113994172

chr2-97724275-C-Achr2-97724275-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP3_Strong

The NM_001079.4(ZAP70):c.239C>A(p.Pro80Gln) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ZAP70 NM_001079.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 7.51

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 Uncertain_significance. Variant got 4 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.969

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZAP70	NM_001079.4	c.239C>A	p.Pro80Gln	missense_variant	3/14	ENST00000264972.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZAP70	ENST00000264972.10	c.239C>A	p.Pro80Gln	missense_variant	3/14	1	NM_001079.4	P1
ZAP70	ENST00000698508.1	c.239C>A	p.Pro80Gln	missense_variant	2/13			P1
ZAP70	ENST00000483781.5	n.432C>A		non_coding_transcript_exon_variant	3/7	2
ZAP70	ENST00000698509.1	n.379C>A		non_coding_transcript_exon_variant	1/12

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1451000 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 721668

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

ZAP70-Related Severe Combined Immunodeficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 08, 2021

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this variant affects ZAP70 protein function (PMID: 10574909). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). ClinVar contains an entry for this variant (Variation ID: 38914). This variant is also known as 448C>A. This variant has been observed in individual(s) with CD8 deficiency (PMID: 10574909). This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with glutamine at codon 80 of the ZAP70 protein (p.Pro80Gln). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and glutamine. -

Combined immunodeficiency due to ZAP70 deficiency Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.87	D
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Benign	-0.58	T
MutationAssessor	Uncertain	2.9	M
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.020	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.81		Gain of ubiquitination at K75 (P = 0.0725);
MVP		0.92
MPC		1.7
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.95
gMVP		0.85

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: rs113994172; hg19: chr2-98340738;