2-97735466-G-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP3BP6BS1

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

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]

ZAP70 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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 the male GnomAd4 subpopulation. Median coverage is 34. This position FAILED quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZAP70	NM_001079.4 link	c.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
ZAP70	ENST00000264972.10 link	c.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.:

Cov.:

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

GnomAD2 exomes

AF:

0.000233

AC:

AN:

244248

AF XY:

0.000233

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 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.:

Cov.:

AF XY:

0.0000818

AC XY:

AN XY:

721022

show subpopulations

Gnomad4 AFR exome

AF:

0.00165

AC:

AN:

33322

Gnomad4 AMR exome

AF:

0.000494

AC:

AN:

44524

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

25912

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39476

Gnomad4 SAS exome

AF:

0.00

AC:

AN:

86000

Gnomad4 FIN exome

AF:

0.0000194

AC:

AN:

51482

Gnomad4 NFE exome

AF:

0.0000262

AC:

AN:

1105934

Gnomad4 Remaining exome

AF:

0.000317

AC:

AN:

59952

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Variant carriers

<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:

0.000854

AC:

130

AN:

152244

Hom.:

Cov.:

AF XY:

0.000860

AC XY:

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.00270

AC:

0.00269594

AN:

0.00269594

Gnomad4 AMR

AF:

0.000849

AC:

0.000849229

AN:

0.000849229

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.000208

AC:

0.000207987

AN:

0.000207987

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.0000294

AC:

0.0000294109

AN:

0.0000294109

Gnomad4 OTH

AF:

0.000474

AC:

0.000473934

AN:

0.000473934

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Variant carriers

<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:

0.000555

Hom.:

Bravo

AF:

0.00101

Asia WGS

AF:

0.000289

AC:

AN:

3478

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

Sep 01, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Combined immunodeficiency due to ZAP70 deficiency

Uncertain:1

Nov 20, 2019

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

ZAP70-Related Severe Combined Immunodeficiency

Benign:1

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

ZAP70-related disorder

Benign:1

Jan 04, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This 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

DANN

Benign

0.66

Mutation Taster

=100/0

polymorphism

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over