rs730880318

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_001079.4(ZAP70):​c.1624-11G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

ZAP70
NM_001079.4 intron

Scores

2
Splicing: ADA: 0.01563
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5O:1

Conservation

PhyloP100: 0.996
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 2-97737984-G-A is Pathogenic according to our data. Variant chr2-97737984-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 13253.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-97737984-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ZAP70NM_001079.4 linkuse as main transcriptc.1624-11G>A intron_variant ENST00000264972.10 NP_001070.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ZAP70ENST00000264972.10 linkuse as main transcriptc.1624-11G>A intron_variant 1 NM_001079.4 ENSP00000264972.5 P43403-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152116
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000399
AC:
1
AN:
250846
Hom.:
0
AF XY:
0.00000737
AC XY:
1
AN XY:
135616
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:
0.00000882
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000616
AC:
9
AN:
1461738
Hom.:
0
Cov.:
41
AF XY:
0.00000688
AC XY:
5
AN XY:
727168
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000719
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152116
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74298
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:5Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Jun 11, 2016- -
Pathogenic, criteria provided, single submitterclinical testingBlueprint GeneticsFeb 16, 2017- -
Combined immunodeficiency due to ZAP70 deficiency Pathogenic:1Other:1
Pathogenic, no assertion criteria providedliterature onlyOMIMMar 11, 1994- -
not provided, no classification providedliterature onlyGeneReviews-- -
ZAP70-Related Severe Combined Immunodeficiency Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJul 16, 2023This sequence change falls in intron 12 of the ZAP70 gene. It does not directly change the encoded amino acid sequence of the ZAP70 protein. RNA analysis indicates that this variant induces altered splicing and likely results in the gain of 3 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is present in population databases (rs730880318, gnomAD 0.0009%). This variant has been observed in individual(s) with ZAP70 deficiency (PMID: 8124727, 27448562). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13253). Studies have shown that this variant alters ZAP70 gene expression (PMID: 8124727). Studies have shown that this variant results in the activation of a cryptic splice site in intron 12 (PMID: 8124727). For these reasons, this variant has been classified as Pathogenic. -
ZAP70-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesOct 12, 2022The ZAP70 c.1624-11G>A variant is predicted to interfere with splicing. This variant has been previously reported in individuals with T-cell defects immunodeficiency (Figure 5, Arpaia et al. 1994. PubMed ID: 8124727) and is observed at a higher prevalence in the Canadian Mennonite population (Schroeder et al. 2016. PubMed ID: 27448562; https://www.ncbi.nlm.nih.gov/books/NBK20221). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-98354447-G-A). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.83
CADD
Uncertain
25
DANN
Benign
0.32

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.016
SpliceAI score (max)
0.99
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.99
Position offset: 2
DS_AL_spliceai
0.34
Position offset: 11

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.

Other links and lift over

dbSNP: rs730880318; hg19: chr2-98354447; API