rs150096962
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Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM2BP4_ModerateBP6BP7BS1
The NM_001079.4(ZAP70):c.1656C>T(p.Ile552=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000523 in 1,613,230 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00037 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00054 ( 0 hom. )
Consequence
ZAP70
NM_001079.4 synonymous
NM_001079.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.425
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 Likely_benign. Variant got -6 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.46).
BP6
?
Variant 2-97738027-C-T is Benign according to our data. Variant chr2-97738027-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 471241.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}. Variant chr2-97738027-C-T is described in Lovd as [Likely_benign].
BP7
?
Synonymous conserved (PhyloP=-0.425 with no splicing effect.
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000375 (57/152142) while in subpopulation NFE AF= 0.00075 (51/68014). AF 95% confidence interval is 0.000586. There are 0 homozygotes in gnomad4. There are 22 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ZAP70 | NM_001079.4 | c.1656C>T | p.Ile552= | synonymous_variant | 13/14 | ENST00000264972.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ZAP70 | ENST00000264972.10 | c.1656C>T | p.Ile552= | synonymous_variant | 13/14 | 1 | NM_001079.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000375 AC: 57AN: 152142Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000356 AC: 89AN: 249682Hom.: 0 AF XY: 0.000355 AC XY: 48AN XY: 135080
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GnomAD4 exome AF: 0.000539 AC: 787AN: 1461088Hom.: 0 Cov.: 41 AF XY: 0.000543 AC XY: 395AN XY: 726862
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GnomAD4 genome ? AF: 0.000375 AC: 57AN: 152142Hom.: 0 Cov.: 33 AF XY: 0.000296 AC XY: 22AN XY: 74316
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:4
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Benign:3
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2022 | ZAP70: BP4, BP7 - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
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. - |
ZAP70-Related Severe Combined Immunodeficiency Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 22, 2024 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at