rs17488834

Variant names:

• chr2-97737676-G-T
• rs17488834
• NM_001079.4:c.1482+11G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001079.4(ZAP70):​c.1482+11G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.327 in 1,613,806 control chromosomes in the GnomAD database, including 94,952 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (7094 hom., cov: 33)
  • Exomes 𝑓: 0.33 (87858 hom.)
• Consequence: ZAP70 NM_001079.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.854
• Publications: 9 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 2-97737676-G-T is Benign according to our data. Variant chr2-97737676-G-T is described in ClinVar as Benign. ClinVar VariationId is 137940.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.353 is higher than 0.05.

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.1482+11G>T		intron	N/A	NP_001070.2
	ZAP70	NM_001378594.1		c.1482+11G>T		intron	N/A	NP_001365523.1	P43403-1
	ZAP70	NM_207519.2		c.561+11G>T		intron	N/A	NP_997402.1	P43403-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZAP70	ENST00000264972.10	TSL:1 MANE Select	c.1482+11G>T		intron	N/A	ENSP00000264972.5	P43403-1
	ZAP70	ENST00000451498.2	TSL:1	c.561+11G>T		intron	N/A	ENSP00000400475.2	P43403-2
	ZAP70	ENST00000463643.5	TSL:1	n.1343+11G>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.263 AC: 40054 AN: 152008 Hom.: 7086 Cov.: 33

Gnomad AFR AF: 0.0632

Gnomad AMI AF: 0.427

Gnomad AMR AF: 0.307

Gnomad ASJ AF: 0.189

Gnomad EAS AF: 0.111

Gnomad SAS AF: 0.128

Gnomad FIN AF: 0.542

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.357

Gnomad OTH AF: 0.237

GnomAD2 exomes AF: 0.305 AC: 76478 AN: 250920 AF XY: 0.298

Gnomad AFR exome AF: 0.0571

Gnomad AMR exome AF: 0.384

Gnomad ASJ exome AF: 0.202

Gnomad EAS exome AF: 0.119

Gnomad FIN exome AF: 0.531

Gnomad NFE exome AF: 0.358

Gnomad OTH exome AF: 0.299

GnomAD4 exome AF: 0.334 AC: 487832 AN: 1461680 Hom.: 87858 Cov.: 57 AF XY: 0.327 AC XY: 237871 AN XY: 727130

African (AFR) AF: 0.0519 AC: 1739 AN: 33480

American (AMR) AF: 0.375 AC: 16757 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.206 AC: 5396 AN: 26134

East Asian (EAS) AF: 0.0983 AC: 3903 AN: 39698

South Asian (SAS) AF: 0.141 AC: 12134 AN: 86256

European-Finnish (FIN) AF: 0.525 AC: 28010 AN: 53312

Middle Eastern (MID) AF: 0.162 AC: 935 AN: 5768

European-Non Finnish (NFE) AF: 0.361 AC: 401455 AN: 1111946

Other (OTH) AF: 0.290 AC: 17503 AN: 60392

GnomAD4 genome AF: 0.263 AC: 40064 AN: 152126 Hom.: 7094 Cov.: 33 AF XY: 0.269 AC XY: 20023 AN XY: 74384

African (AFR) AF: 0.0630 AC: 2617 AN: 41526

American (AMR) AF: 0.308 AC: 4702 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.189 AC: 655 AN: 3468

East Asian (EAS) AF: 0.110 AC: 573 AN: 5188

South Asian (SAS) AF: 0.128 AC: 616 AN: 4824

European-Finnish (FIN) AF: 0.542 AC: 5729 AN: 10576

Middle Eastern (MID) AF: 0.194 AC: 57 AN: 294

European-Non Finnish (NFE) AF: 0.357 AC: 24232 AN: 67954

Other (OTH) AF: 0.234 AC: 494 AN: 2108

Alfa AF: 0.284 Hom.: 3376

Bravo AF: 0.243

Asia WGS AF: 0.133 AC: 460 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Combined immunodeficiency due to ZAP70 deficiency (1)
-	-	1	not provided (1)
-	-	1	ZAP70-Related Severe Combined Immunodeficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.0060
DANN	Benign	0.38
PhyloP100		-0.85
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs17488834; hg19: chr2-98354139; COSMIC: COSV53853255; COSMIC: COSV53853255;