2-97734709-G-T

Variant names:

• chr2-97734709-G-T
• rs869025224
• NM_001079.4:c.1079G>T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_001079.4(ZAP70):​c.1079G>T​(p.Arg360Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R360P) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ZAP70 NM_001079.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.42

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_pathogenic. Variant got 6 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-97734709-G-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZAP70	NM_001079.4	c.1079G>T	p.Arg360Leu	missense_variant	Exon 9 of 14	ENST00000264972.10	NP_001070.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZAP70	ENST00000264972.10	c.1079G>T	p.Arg360Leu	missense_variant	Exon 9 of 14	1	NM_001079.4	ENSP00000264972.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Benign	-0.023	T
BayesDel_noAF	Benign	-0.27
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.023	T
MetaRNN	Uncertain	0.51	D;D
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	0.070	N;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-2.7	D;D
REVEL	Benign	0.20
Sift	Benign	0.15	T;T
Sift4G	Benign	0.17	T;T
Polyphen		0.93	P;.
Vest4		0.65
MutPred		0.49		Loss of solvent accessibility (P = 0.0098);.;
MVP		0.77
MPC		1.7
ClinPred		0.98	D
GERP RS		5.4
Varity_R		0.41
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs869025224; hg19: chr2-98351172;