rs1677267957

Variant names:

• chr2-97724052-G-A
• rs1677267957
• NM_001079.4:c.16G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001079.4(ZAP70):​c.16G>A​(p.Ala6Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000214 in 1,401,386 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A6V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ZAP70 NM_001079.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.34
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27055597).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001079.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZAP70	NM_001079.4	MANE Select	c.16G>A	p.Ala6Thr	missense	Exon 3 of 14	NP_001070.2
	ZAP70	NM_001378594.1		c.16G>A	p.Ala6Thr	missense	Exon 2 of 13	NP_001365523.1	P43403-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZAP70	ENST00000264972.10	TSL:1 MANE Select	c.16G>A	p.Ala6Thr	missense	Exon 3 of 14	ENSP00000264972.5	P43403-1
	ZAP70	ENST00000698508.2		c.16G>A	p.Ala6Thr	missense	Exon 2 of 13	ENSP00000513759.1	P43403-1
	ZAP70	ENST00000885386.1		c.16G>A	p.Ala6Thr	missense	Exon 3 of 14	ENSP00000555445.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000214 AC: 3 AN: 1401386 Hom.: 0 Cov.: 32 AF XY: 0.00000288 AC XY: 2 AN XY: 693524

African (AFR) AF: 0.00 AC: 0 AN: 32206

American (AMR) AF: 0.00 AC: 0 AN: 38122

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25316

East Asian (EAS) AF: 0.0000815 AC: 3 AN: 36814

South Asian (SAS) AF: 0.00 AC: 0 AN: 80332

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38180

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4558

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1087550

Other (OTH) AF: 0.00 AC: 0 AN: 58308

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	ZAP70-Related Severe Combined Immunodeficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.023	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T
Eigen	Benign	0.058
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	0.84	L
PhyloP100		4.3
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.55	N
REVEL	Benign	0.078
Sift	Benign	0.56	T
Sift4G	Benign	0.58	T
Polyphen		0.47	P
Vest4		0.42
MutPred		0.21		Gain of glycosylation at A6 (P = 0.0107)
MVP		0.76
MPC		0.74
ClinPred		0.63	D
GERP RS		5.0
Varity_R		0.34
gMVP		0.25
Mutation Taster		=57/43	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: rs1677267957; hg19: chr2-98340515;