rs730880318
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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
NM_001079.4 intron
Scores
2
Splicing: ADA: 0.01563
1
Clinical Significance
Conservation
PhyloP100: 0.996
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]
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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 |
---|---|---|---|---|---|---|---|---|
ZAP70 | NM_001079.4 | c.1624-11G>A | intron_variant | ENST00000264972.10 | NP_001070.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ZAP70 | ENST00000264972.10 | c.1624-11G>A | intron_variant | 1 | NM_001079.4 | ENSP00000264972.5 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152116Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250846Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135616
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GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461738Hom.: 0 Cov.: 41 AF XY: 0.00000688 AC XY: 5AN XY: 727168
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152116Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74298
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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 submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 11, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Feb 16, 2017 | - - |
Combined immunodeficiency due to ZAP70 deficiency Pathogenic:1Other:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 11, 1994 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
ZAP70-Related Severe Combined Immunodeficiency Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 16, 2023 | This 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 submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 12, 2022 | The 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
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Name
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BayesDel_noAF
Benign
CADD
Uncertain
DANN
Benign
Splicing
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dbscSNV1_ADA
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: 2
DS_AL_spliceai
Position offset: 11
Find out detailed SpliceAI scores and Pangolin per-transcript scores at