chr2-97734655-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_001079.4(ZAP70):c.1025T>C(p.Ile342Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000504 in 1,614,194 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. I342I) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00062 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00049 ( 0 hom. )

Consequence

ZAP70
NM_001079.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:2

Conservation

PhyloP100: 2.42

Publications

5 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: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen

ZAP70 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_001079.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00992161).

BP6

Variant 2-97734655-T-C is Benign according to our data. Variant chr2-97734655-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 337634.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000624 (95/152350) while in subpopulation NFE AF = 0.000706 (48/68022). AF 95% confidence interval is 0.000547. There are 0 homozygotes in GnomAd4. There are 43 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001079.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ZAP70	NM_001079.4	MANE Select	c.1025T>C	p.Ile342Thr	missense	Exon 9 of 14	NP_001070.2
ZAP70	NM_001378594.1		c.1025T>C	p.Ile342Thr	missense	Exon 8 of 13	NP_001365523.1	P43403-1
ZAP70	NM_207519.2		c.104T>C	p.Ile35Thr	missense	Exon 1 of 6	NP_997402.1	P43403-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ZAP70	ENST00000264972.10	TSL:1 MANE Select	c.1025T>C	p.Ile342Thr	missense	Exon 9 of 14	ENSP00000264972.5	P43403-1
ZAP70	ENST00000451498.2	TSL:1	c.104T>C	p.Ile35Thr	missense	Exon 1 of 6	ENSP00000400475.2	P43403-2
ZAP70	ENST00000463643.5	TSL:1	n.886T>C		non_coding_transcript_exon	Exon 8 of 13

Frequencies

GnomAD3 genomes

AF:

0.000631

AC:

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.0275

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.000620

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000706

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.000374

AC:

AN:

251330

AF XY:

0.000383

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000660

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000491

AC:

718

AN:

1461844

Hom.:

Cov.:

AF XY:

0.000520

AC XY:

378

AN XY:

727222

show subpopulations

African (AFR)

AF:

0.000239

AC:

AN:

33480

American (AMR)

AF:

0.000313

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.000151

AC:

AN:

39700

South Asian (SAS)

AF:

0.000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53380

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000578

AC:

643

AN:

1112006

Other (OTH)

AF:

0.000596

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

105

157

210

262

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

<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:

0.000624

AC:

AN:

152350

Hom.:

Cov.:

AF XY:

0.000577

AC XY:

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.000192

AC:

AN:

41588

American (AMR)

AF:

0.000457

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000386

AC:

AN:

5186

South Asian (SAS)

AF:

0.000621

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000706

AC:

AN:

68022

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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:

0.000423

Hom.:

Bravo

AF:

0.000597

EpiCase

AF:

0.000600

EpiControl

AF:

0.000830

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Combined immunodeficiency due to ZAP70 deficiency (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.23

CADD

Uncertain

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.34

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.020

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.80

M_CAP

Benign

0.053

MetaRNN

Benign

0.0099

MetaSVM

Benign

-0.51

MutationAssessor

Benign

0.26

PhyloP100

2.4

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.15

REVEL

Uncertain

0.30

Sift

Benign

0.67

Sift4G

Benign

0.48

PromoterAI

-0.031

Neutral

(source)

Varity_R

0.31

gMVP

0.86

Mutation Taster

=46/54

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over