2-97735466-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP6BS1

The NM_001079.4(ZAP70):​c.1289+10G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000164 in 1,604,568 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 0.00085 ( 0 hom., cov: 34)
Exomes 𝑓: 0.000092 ( 0 hom. )

Consequence

ZAP70
NM_001079.4 intron

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: -0.396
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 Likely_benign. Variant got -3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP6
Variant 2-97735466-G-A is Benign according to our data. Variant chr2-97735466-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 538573.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1}.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000854 (130/152244) while in subpopulation AFR AF= 0.0027 (112/41544). AF 95% confidence interval is 0.00229. There are 0 homozygotes in gnomad4. There are 64 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ZAP70NM_001079.4 linkc.1289+10G>A intron_variant Intron 10 of 13 ENST00000264972.10 NP_001070.2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ZAP70ENST00000264972.10 linkc.1289+10G>A intron_variant Intron 10 of 13 1 NM_001079.4 ENSP00000264972.5 P43403-1

Frequencies

GnomAD3 genomes
AF:
0.000848
AC:
129
AN:
152126
Hom.:
0
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.00268
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000850
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000208
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.000479
GnomAD3 exomes
AF:
0.000233
AC:
57
AN:
244248
Hom.:
0
AF XY:
0.000233
AC XY:
31
AN XY:
132806
show subpopulations
Gnomad AFR exome
AF:
0.00218
Gnomad AMR exome
AF:
0.000407
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:
0.0000545
Gnomad OTH exome
AF:
0.000502
GnomAD4 exome
AF:
0.0000916
AC:
133
AN:
1452324
Hom.:
0
Cov.:
35
AF XY:
0.0000818
AC XY:
59
AN XY:
721022
show subpopulations
Gnomad4 AFR exome
AF:
0.00165
Gnomad4 AMR exome
AF:
0.000494
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000194
Gnomad4 NFE exome
AF:
0.0000262
Gnomad4 OTH exome
AF:
0.000317
GnomAD4 genome
AF:
0.000854
AC:
130
AN:
152244
Hom.:
0
Cov.:
34
AF XY:
0.000860
AC XY:
64
AN XY:
74448
show subpopulations
Gnomad4 AFR
AF:
0.00270
Gnomad4 AMR
AF:
0.000849
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000208
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.000474
Alfa
AF:
0.000555
Hom.:
0
Bravo
AF:
0.00101
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Combined immunodeficiency due to ZAP70 deficiency Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingBaylor GeneticsNov 20, 2019This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicSep 01, 2021- -
ZAP70-Related Severe Combined Immunodeficiency Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 13, 2025- -
ZAP70-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesJan 04, 2024This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.80
CADD
Benign
18
DANN
Benign
0.66

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.53
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.53
Position offset: 1

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: rs200538234; hg19: chr2-98351929; API