chr2-97739787-G-C

Position:

• chr2-97739787-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001079.4(ZAP70):​c.*289G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.125 in 470,936 control chromosomes in the GnomAD database, including 4,247 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1828 hom., cov: 33)
  • Exomes 𝑓: 0.12 (2419 hom.)
• Consequence: ZAP70 NM_001079.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.349

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 2-97739787-G-C is Benign according to our data. Variant chr2-97739787-G-C is described in ClinVar as [Benign]. Clinvar id is 337642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.222 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZAP70	NM_001079.4	c.*289G>C		3_prime_UTR_variant	14/14	ENST00000264972.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZAP70	ENST00000264972.10	c.*289G>C		3_prime_UTR_variant	14/14	1	NM_001079.4	P1
ZAP70	ENST00000463643.5	n.2010G>C		non_coding_transcript_exon_variant	13/13	1
ZAP70	ENST00000698508.1	c.*289G>C		3_prime_UTR_variant	13/13			P1
ZAP70	ENST00000487283.5	n.3201G>C		non_coding_transcript_exon_variant	7/7	2

Frequencies

GnomAD3 genomes AF: 0.142 AC: 21611 AN: 152048 Hom.: 1826 Cov.: 33

Gnomad AFR AF: 0.226

Gnomad AMI AF: 0.212

Gnomad AMR AF: 0.102

Gnomad ASJ AF: 0.136

Gnomad EAS AF: 0.149

Gnomad SAS AF: 0.0948

Gnomad FIN AF: 0.0529

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.116

Gnomad OTH AF: 0.159

GnomAD4 exome AF: 0.116 AC: 37017 AN: 318770 Hom.: 2419 Cov.: 3 AF XY: 0.116 AC XY: 19122 AN XY: 165160

Gnomad4 AFR exome AF: 0.222

Gnomad4 AMR exome AF: 0.0932

Gnomad4 ASJ exome AF: 0.119

Gnomad4 EAS exome AF: 0.145

Gnomad4 SAS exome AF: 0.0991

Gnomad4 FIN exome AF: 0.0615

Gnomad4 NFE exome AF: 0.116

Gnomad4 OTH exome AF: 0.123

GnomAD4 genome AF: 0.142 AC: 21620 AN: 152166 Hom.: 1828 Cov.: 33 AF XY: 0.139 AC XY: 10307 AN XY: 74406

Gnomad4 AFR AF: 0.226

Gnomad4 AMR AF: 0.102

Gnomad4 ASJ AF: 0.136

Gnomad4 EAS AF: 0.148

Gnomad4 SAS AF: 0.0949

Gnomad4 FIN AF: 0.0529

Gnomad4 NFE AF: 0.115

Gnomad4 OTH AF: 0.157

Alfa AF: 0.128 Hom.: 195

Bravo AF: 0.153

Asia WGS AF: 0.0970 AC: 336 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Combined immunodeficiency due to ZAP70 deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 07, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.94
DANN	Benign	0.72

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

LitVar

Other links and lift over

dbSNP: rs2278699; hg19: chr2-98356250;