Genetic Variant ZAP70:c.-22+1064G>C (chr2-97715058-G-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001079.4(ZAP70):c.-22+1064G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.186 in 152,108 control chromosomes in the GnomAD database, including 2,909 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.19 ( 2909 hom., cov: 32)

Consequence

ZAP70
NM_001079.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.121

Publications

9 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)

ZAP70 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.95).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.216 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZAP70	NM_001079.4 link	c.-22+1064G>C		intron_variant	Intron 2 of 13	ENST00000264972.10	NP_001070.2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
ZAP70	ENST00000264972.10 link	c.-22+1064G>C	intron_variant	Intron 2 of 13	1	NM_001079.4	ENSP00000264972.5	P43403-1
ZAP70	ENST00000698508.2 link	c.-22+1064G>C	intron_variant	Intron 1 of 12			ENSP00000513759.1	P43403-1
ZAP70	ENST00000483781.5 link	n.172+1064G>C	intron_variant	Intron 2 of 6	2
ZAP70	ENST00000718250.1 link	n.-22+1064G>C	intron_variant	Intron 2 of 13			ENSP00000520695.1

Frequencies

GnomAD3 genomes

AF:

0.186

AC:

28344

AN:

151990

Hom.:

2910

Cov.:

show subpopulations

Gnomad AFR

AF:

0.157

Gnomad AMI

AF:

0.316

Gnomad AMR

AF:

0.206

Gnomad ASJ

AF:

0.218

Gnomad EAS

AF:

0.0993

Gnomad SAS

AF:

0.0742

Gnomad FIN

AF:

0.120

Gnomad MID

AF:

0.301

Gnomad NFE

AF:

0.219

Gnomad OTH

AF:

0.240

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.186

AC:

28346

AN:

152108

Hom.:

2909

Cov.:

AF XY:

0.181

AC XY:

13459

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.157

AC:

6524

AN:

41490

American (AMR)

AF:

0.206

AC:

3141

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.218

AC:

755

AN:

3468

East Asian (EAS)

AF:

0.0993

AC:

513

AN:

5164

South Asian (SAS)

AF:

0.0740

AC:

356

AN:

4808

European-Finnish (FIN)

AF:

0.120

AC:

1274

AN:

10602

Middle Eastern (MID)

AF:

0.289

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.219

AC:

14909

AN:

67982

Other (OTH)

AF:

0.238

AC:

501

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1150

2300

3450

4600

5750

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

284

568

852

1136

1420

<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:

0.0957

Hom.:

142

Bravo

AF:

0.193

Asia WGS

AF:

0.135

AC:

472

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.95

CADD

Benign

2.2

(source)

DANN

Benign

0.37

PhyloP100

-0.12

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over