2-97724061-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001079.4(ZAP70):c.25C>G(p.Pro9Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000427 in 1,405,194 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 0.0000043 ( 0 hom. )

Consequence

ZAP70
NM_001079.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.52

Variant links:

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]

ZAP70 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.81

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZAP70	NM_001079.4 linkuse as main transcript	c.25C>G	p.Pro9Ala	missense_variant	3/14	ENST00000264972.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZAP70	ENST00000264972.10 linkuse as main transcript	c.25C>G	p.Pro9Ala	missense_variant	3/14	1	NM_001079.4	P1	P43403-1
ZAP70	ENST00000698508.1 linkuse as main transcript	c.25C>G	p.Pro9Ala	missense_variant	2/13			P1	P43403-1
ZAP70	ENST00000483781.5 linkuse as main transcript	n.218C>G		non_coding_transcript_exon_variant	3/7	2
ZAP70	ENST00000698509.1 linkuse as main transcript	n.165C>G		non_coding_transcript_exon_variant	1/12

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000605

AC:

AN:

165326

Hom.:

AF XY:

0.00

AC XY:

AN XY:

90540

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000144

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000427

AC:

AN:

1405194

Hom.:

Cov.:

AF XY:

0.00000288

AC XY:

AN XY:

695630

show subpopulations

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:

0.00000459

Gnomad4 OTH exome

AF:

0.0000171

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000847

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

ZAP70-Related Severe Combined Immunodeficiency

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 08, 2022

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. 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: 1399829). This variant has not been reported in the literature in individuals affected with ZAP70-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 9 of the ZAP70 protein (p.Pro9Ala). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Uncertain

0.034

BayesDel_noAF

Benign

-0.19

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.60

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.027

MetaRNN

Pathogenic

0.81

MetaSVM

Benign

-0.71

MutationAssessor

Benign

2.0

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-3.2

REVEL

Benign

0.28

Sift

Uncertain

0.0080

Sift4G

Uncertain

0.039

Polyphen

1.0

Vest4

0.83

MutPred

0.52

Loss of glycosylation at P9 (P = 0.0706);

MVP

0.72

MPC

1.7

ClinPred

0.93

GERP RS

5.0

Varity_R

0.64

gMVP

0.78

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over