NM_001079.4:c.1737-3C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001079.4(ZAP70):​c.1737-3C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00177 in 1,613,378 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0010 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0019 ( 3 hom. )

Consequence

ZAP70
NM_001079.4 splice_region, intron

Scores

2
Splicing: ADA: 0.007540
2

Clinical Significance

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

Conservation

PhyloP100: 1.75

Publications

0 publications found
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 Gene-Disease associations (from GenCC):
  • combined immunodeficiency due to ZAP70 deficiency
    Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.65).
BP6
Variant 2-97739372-C-T is Benign according to our data. Variant chr2-97739372-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 337638.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
BS1
Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00101 (154/152372) while in subpopulation NFE AF = 0.00171 (116/68030). AF 95% confidence interval is 0.00145. There are 0 homozygotes in GnomAd4. There are 70 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
BS2
High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ZAP70NM_001079.4 linkc.1737-3C>T splice_region_variant, intron_variant Intron 13 of 13 ENST00000264972.10 NP_001070.2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ZAP70ENST00000264972.10 linkc.1737-3C>T splice_region_variant, intron_variant Intron 13 of 13 1 NM_001079.4 ENSP00000264972.5 P43403-1

Frequencies

GnomAD3 genomes
AF:
0.00100
AC:
153
AN:
152254
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000531
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000458
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00103
Gnomad FIN
AF:
0.000188
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00170
Gnomad OTH
AF:
0.000478
GnomAD2 exomes
AF:
0.000866
AC:
214
AN:
247054
AF XY:
0.000923
show subpopulations
Gnomad AFR exome
AF:
0.000375
Gnomad AMR exome
AF:
0.000695
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000926
Gnomad NFE exome
AF:
0.00143
Gnomad OTH exome
AF:
0.000494
GnomAD4 exome
AF:
0.00185
AC:
2709
AN:
1461006
Hom.:
3
Cov.:
31
AF XY:
0.00186
AC XY:
1354
AN XY:
726836
show subpopulations
African (AFR)
AF:
0.000269
AC:
9
AN:
33472
American (AMR)
AF:
0.000626
AC:
28
AN:
44708
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26122
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.000673
AC:
58
AN:
86236
European-Finnish (FIN)
AF:
0.000132
AC:
7
AN:
52844
Middle Eastern (MID)
AF:
0.000694
AC:
4
AN:
5760
European-Non Finnish (NFE)
AF:
0.00228
AC:
2535
AN:
1111796
Other (OTH)
AF:
0.00113
AC:
68
AN:
60368
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.482
Heterozygous variant carriers
0
179
359
538
718
897
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
106
212
318
424
530
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.00101
AC:
154
AN:
152372
Hom.:
0
Cov.:
33
AF XY:
0.000940
AC XY:
70
AN XY:
74504
show subpopulations
African (AFR)
AF:
0.000529
AC:
22
AN:
41590
American (AMR)
AF:
0.000457
AC:
7
AN:
15312
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5188
South Asian (SAS)
AF:
0.00124
AC:
6
AN:
4832
European-Finnish (FIN)
AF:
0.000188
AC:
2
AN:
10628
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.00171
AC:
116
AN:
68030
Other (OTH)
AF:
0.000473
AC:
1
AN:
2114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.502
Heterozygous variant carriers
0
10
19
29
38
48
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
4
8
12
16
20
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00130
Hom.:
0
Bravo
AF:
0.00106
Asia WGS
AF:
0.00115
AC:
4
AN:
3478
EpiCase
AF:
0.00142
EpiControl
AF:
0.00190

ClinVar

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

Submissions by phenotype

not provided Uncertain:1
Jun 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

ZAP70: PM2, BP4 -

Combined immunodeficiency due to ZAP70 deficiency Uncertain:1
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:1
Jul 30, 2021
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Variant summary: ZAP70 c.1737-3C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00087 in 247054 control chromosomes, predominantly at a frequency of 0.0014 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in ZAP70 causing Severe Combined Immunodeficiency Syndrome phenotype (0.00035), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.1737-3C>T in individuals affected with Severe Combined Immunodeficiency Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as benign. -

ZAP70-Related Severe Combined Immunodeficiency Benign:1
Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.65
CADD
Benign
14
DANN
Benign
0.58
PhyloP100
1.8
Mutation Taster
=92/8
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.0075
dbscSNV1_RF
Benign
0.18
SpliceAI score (max)
0.11
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs56249179; hg19: chr2-98355835; API