chr2-97734655-T-C

Position:

• chr2-97734655-T-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 4P and 9B. PM1 PM2 BP4_Strong BP6 BS1

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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00062 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00049 (0 hom.)
• Consequence: ZAP70 NM_001079.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:2
• Conservation: PhyloP100: 2.42

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• PM1: In a domain Protein kinase (size 262) in uniprot entity ZAP70_HUMAN there are 9 pathogenic changes around while only 1 benign (90%) in NM_001079.4
• PM2: Very rare variant in population databases, with high coverage
• 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 id is 337634.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=4}.
• 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZAP70	NM_001079.4	c.1025T>C	p.Ile342Thr	missense_variant	9/14	ENST00000264972.10	NP_001070.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZAP70	ENST00000264972.10	c.1025T>C	p.Ile342Thr	missense_variant	9/14	1	NM_001079.4	ENSP00000264972	P1

Frequencies

GnomAD3 genomes AF: 0.000631 AC: 96 AN: 152232 Hom.: 0 Cov.: 33

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

GnomAD3 exomes AF: 0.000374 AC: 94 AN: 251330 Hom.: 0 AF XY: 0.000383 AC XY: 52 AN XY: 135846

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 SAS exome AF: 0.0000653

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.: 0 Cov.: 31 AF XY: 0.000520 AC XY: 378 AN XY: 727222

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000578

Gnomad4 OTH exome AF: 0.000596

GnomAD4 genome AF: 0.000624 AC: 95 AN: 152350 Hom.: 0 Cov.: 33 AF XY: 0.000577 AC XY: 43 AN XY: 74494

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000706

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000517 Hom.: 0

Bravo AF: 0.000597

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000305 AC: 37

EpiCase AF: 0.000600

EpiControl AF: 0.000830

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 08, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 03, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 15, 2020	- -

Combined immunodeficiency due to ZAP70 deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 22, 2023

Variant summary: ZAP70 c.1025T>C (p.Ile342Thr) results in a non-conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00037 in 251330 control chromosomes, predominantly at a frequency of 0.00066 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in ZAP70 causing Severe Combined Immunodeficiency phenotype (0.00035), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.1025T>C in individuals affected with Severe Combined Immunodeficiency and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=3) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign. -

ZAP70-Related Severe Combined Immunodeficiency Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	23
DANN	Benign	0.85
DEOGEN2	Benign	0.34	T;.
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.020
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.80	T;T
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.0099	T;T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	0.26	N;.
MutationTaster	Benign	0.90	D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.15	N;N
REVEL	Uncertain	0.30
Sift	Benign	0.67	T;T
Sift4G	Benign	0.48	T;T
Polyphen		0.27	B;.
Vest4		0.39
MVP		0.98
MPC		1.1
ClinPred		0.030	T
GERP RS		5.4
Varity_R		0.31
gMVP		0.86

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

Publications

LitVar

Other links and lift over

dbSNP: rs142702703; hg19: chr2-98351118;