rs145955907

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_001079.4(ZAP70):c.464C>T(p.Thr155Met) variant causes a missense change. The variant allele was found at a frequency of 0.00121 in 1,614,160 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0021 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 21 hom. )

Consequence

ZAP70
NM_001079.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 5.83

Publications

7 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013161004).

BP6

Variant 2-97725153-C-T is Benign according to our data. Variant chr2-97725153-C-T is described in ClinVar as Benign. ClinVar VariationId is 538570.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00209 (318/152302) while in subpopulation NFE AF = 0.00115 (78/68020). AF 95% confidence interval is 0.000941. There are 5 homozygotes in GnomAd4. There are 216 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZAP70	NM_001079.4 link	c.464C>T	p.Thr155Met	missense_variant	Exon 4 of 14	ENST00000264972.10	NP_001070.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZAP70	ENST00000264972.10 link	c.464C>T	p.Thr155Met	missense_variant	Exon 4 of 14	1	NM_001079.4	ENSP00000264972.5

Frequencies

GnomAD3 genomes

AF:

0.00209

AC:

318

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0222

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00115

Gnomad OTH

AF:

0.000958

GnomAD2 exomes

AF:

0.00227

AC:

570

AN:

251014

AF XY:

0.00223

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0204

Gnomad NFE exome

AF:

0.00105

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.00112

AC:

1632

AN:

1461858

Hom.:

Cov.:

AF XY:

0.00112

AC XY:

814

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0205

AC:

1096

AN:

53400

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000431

AC:

479

AN:

1112004

Other (OTH)

AF:

0.000878

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

104

208

311

415

519

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.00209

AC:

318

AN:

152302

Hom.:

Cov.:

AF XY:

0.00290

AC XY:

216

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41572

American (AMR)

AF:

0.0000653

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0222

AC:

236

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00115

AC:

AN:

68020

Other (OTH)

AF:

0.000948

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.000746

Hom.:

Bravo

AF:

0.000261

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.00193

AC:

234

EpiCase

AF:

0.000327

EpiControl

AF:

0.000474

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

ZAP70-Related Severe Combined Immunodeficiency

Benign:1

Jan 10, 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

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Benign

-0.066

BayesDel_noAF

Uncertain

0.13

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.76

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.98

MetaRNN

Benign

0.013

MetaSVM

Uncertain

0.67

MutationAssessor

Uncertain

2.3

PhyloP100

5.8

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-3.3

REVEL

Pathogenic

0.66

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.012

Polyphen

1.0

Vest4

0.73

MVP

0.93

MPC

1.8

ClinPred

0.14

GERP RS

5.4

Varity_R

0.45

gMVP

0.54

Mutation Taster

=81/19

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over