2-97724043-G-T

Variant names:

• chr2-97724043-G-T
• NM_001079.4:c.7G>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001079.4(ZAP70):​c.7G>T​(p.Asp3Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000000715 in 1,398,954 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: ZAP70 NM_001079.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.27

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.866

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZAP70	NM_001079.4	c.7G>T	p.Asp3Tyr	missense_variant	Exon 3 of 14	ENST00000264972.10	NP_001070.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZAP70	ENST00000264972.10	c.7G>T	p.Asp3Tyr	missense_variant	Exon 3 of 14	1	NM_001079.4	ENSP00000264972.5
ZAP70	ENST00000698508.1	c.7G>T	p.Asp3Tyr	missense_variant	Exon 2 of 13			ENSP00000513759.1
ZAP70	ENST00000483781.5	n.200G>T		non_coding_transcript_exon_variant	Exon 3 of 7	2
ZAP70	ENST00000698509.1	n.147G>T		non_coding_transcript_exon_variant	Exon 1 of 12

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1398954 Hom.: 0 Cov.: 32 AF XY: 0.00000144 AC XY: 1 AN XY: 692174

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000265

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	0.53	D
MutationAssessor	Pathogenic	3.0	M
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Uncertain	0.64
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.64
MutPred		0.35		Gain of catalytic residue at D3 (P = 0.0544);
MVP		0.93
MPC		1.8
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.88
gMVP		0.84

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-98340506; COSMIC: COSV99385922; COSMIC: COSV99385922;