Variant summary

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

The NM_001079.4(ZAP70):c.1082+8C>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 0.000884 in 1,613,078 control chromosomes in the GnomAD database, including 7 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 0.0029 ( 3 hom., cov: 33)

Exomes 𝑓: 0.00067 ( 4 hom. )

Consequence

ZAP70
NM_001079.4 splice_region, intron

Scores

Splicing: ADA: 0.00004450

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: -1.96

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)

ZAP70 links:

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=-0.9).

BP6

Variant 2-97734720-C-T is Benign according to our data. Variant chr2-97734720-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 471240.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00292 (445/152314) while in subpopulation AFR AF = 0.00926 (385/41566). AF 95% confidence interval is 0.0085. There are 3 homozygotes in GnomAd4. There are 216 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

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	Effect	Exon Rank	Protein
ZAP70	NM_001079.4	MANE Select	c.1082+8C>T	splice_region intron	N/A	NP_001070.2
ZAP70	NM_001378594.1		c.1082+8C>T	splice_region intron	N/A	NP_001365523.1
ZAP70	NM_207519.2		c.161+8C>T	splice_region intron	N/A	NP_997402.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
ZAP70	ENST00000264972.10	TSL:1 MANE Select	c.1082+8C>T	splice_region intron	N/A	ENSP00000264972.5
ZAP70	ENST00000451498.2	TSL:1	c.161+8C>T	splice_region intron	N/A	ENSP00000400475.2
ZAP70	ENST00000463643.5	TSL:1	n.943+8C>T	splice_region intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00289

AC:

440

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00917

Gnomad AMI

AF:

0.0230

Gnomad AMR

AF:

0.000850

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000309

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.000782

AC:

194

AN:

248136

AF XY:

0.000535

show subpopulations

Gnomad AFR exome

AF:

0.00823

Gnomad AMR exome

AF:

0.000376

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000404

Gnomad OTH exome

AF:

0.000328

GnomAD4 exome

AF:

0.000672

AC:

981

AN:

1460764

Hom.:

Cov.:

AF XY:

0.000586

AC XY:

426

AN XY:

726692

show subpopulations

African (AFR)

AF:

0.0103

AC:

344

AN:

33478

American (AMR)

AF:

0.000313

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86240

European-Finnish (FIN)

AF:

0.0000191

AC:

AN:

52478

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000513

AC:

570

AN:

1111882

Other (OTH)

AF:

0.000745

AC:

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

111

167

222

278

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

136

170

<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:

0.00292

AC:

445

AN:

152314

Hom.:

Cov.:

AF XY:

0.00290

AC XY:

216

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.00926

AC:

385

AN:

41566

American (AMR)

AF:

0.000849

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000309

AC:

AN:

68018

Other (OTH)

AF:

0.00189

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

104

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:

0.000742

Hom.:

Bravo

AF:

0.00315

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Autoimmune disease, multisystem, infantile-onset, 2;CN032501:Combined immunodeficiency due to ZAP70 deficiency (1)

Combined immunodeficiency due to ZAP70 deficiency (1)

not provided (1)

ZAP70-Related Severe Combined Immunodeficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.20

(source)

DANN

Benign

0.79

PhyloP100

-2.0

PromoterAI

-0.087

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000044

dbscSNV1_RF

Benign

0.010

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.

NM_001079.4:c.1082+8C>T

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over