2-97724043-G-T

Variant names:

• chr2-97724043-G-T
• rs1009114725
• NM_001079.4:c.7G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The ENST00000264972.10(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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D3H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: ZAP70 ENST00000264972.10 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.27
• Publications: 0 publications found

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)

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000264972.10. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZAP70	NM_001079.4	MANE Select	c.7G>T	p.Asp3Tyr	missense	Exon 3 of 14	NP_001070.2
	ZAP70	NM_001378594.1		c.7G>T	p.Asp3Tyr	missense	Exon 2 of 13	NP_001365523.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZAP70	ENST00000264972.10	TSL:1 MANE Select	c.7G>T	p.Asp3Tyr	missense	Exon 3 of 14	ENSP00000264972.5
	ZAP70	ENST00000698508.2		c.7G>T	p.Asp3Tyr	missense	Exon 2 of 13	ENSP00000513759.1
	ZAP70	ENST00000483781.5	TSL:2	n.200G>T		non_coding_transcript_exon	Exon 3 of 7

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32132

American (AMR) AF: 0.0000265 AC: 1 AN: 37800

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25284

East Asian (EAS) AF: 0.00 AC: 0 AN: 36680

South Asian (SAS) AF: 0.00 AC: 0 AN: 80142

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4432

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1086646

Other (OTH) AF: 0.00 AC: 0 AN: 58238

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		6.3
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
Mutation Taster		=54/46	polymorphism

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

Other links and lift over

dbSNP: rs1009114725; hg19: chr2-98340506; COSMIC: COSV99385922; COSMIC: COSV99385922;