rs3192177

Variant names:

• chr2-97738048-G-A
• rs3192177
• NM_001079.4:c.1677G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001079.4(ZAP70):​c.1677G>A​(p.Glu559Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.321 in 1,611,638 control chromosomes in the GnomAD database, including 91,892 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (6889 hom., cov: 32)
  • Exomes 𝑓: 0.33 (85003 hom.)
• Consequence: ZAP70 NM_001079.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: -0.295
• Publications: 23 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 2-97738048-G-A is Benign according to our data. Variant chr2-97738048-G-A is described in ClinVar as Benign. ClinVar VariationId is 137941.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.295 with no splicing effect.
• 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.1677G>A	p.Glu559Glu	synonymous	Exon 13 of 14	NP_001070.2
	ZAP70	NM_001378594.1		c.1677G>A	p.Glu559Glu	synonymous	Exon 12 of 13	NP_001365523.1	P43403-1
	ZAP70	NM_207519.2		c.756G>A	p.Glu252Glu	synonymous	Exon 5 of 6	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.1677G>A	p.Glu559Glu	synonymous	Exon 13 of 14	ENSP00000264972.5	P43403-1
	ZAP70	ENST00000451498.2	TSL:1	c.756G>A	p.Glu252Glu	synonymous	Exon 5 of 6	ENSP00000400475.2	P43403-2
	ZAP70	ENST00000463643.5	TSL:1	n.1538G>A		non_coding_transcript_exon	Exon 12 of 13

Frequencies

GnomAD3 genomes AF: 0.268 AC: 40743 AN: 151912 Hom.: 6890 Cov.: 32

Gnomad AFR AF: 0.123

Gnomad AMI AF: 0.427

Gnomad AMR AF: 0.232

Gnomad ASJ AF: 0.186

Gnomad EAS AF: 0.00769

Gnomad SAS AF: 0.125

Gnomad FIN AF: 0.537

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.357

Gnomad OTH AF: 0.228

GnomAD2 exomes AF: 0.273 AC: 67253 AN: 246492 AF XY: 0.273

Gnomad AFR exome AF: 0.121

Gnomad AMR exome AF: 0.189

Gnomad ASJ exome AF: 0.201

Gnomad EAS exome AF: 0.00666

Gnomad FIN exome AF: 0.528

Gnomad NFE exome AF: 0.359

Gnomad OTH exome AF: 0.275

GnomAD4 exome AF: 0.327 AC: 476616 AN: 1459610 Hom.: 85003 Cov.: 53 AF XY: 0.321 AC XY: 232951 AN XY: 726020

African (AFR) AF: 0.114 AC: 3817 AN: 33462

American (AMR) AF: 0.193 AC: 8532 AN: 44258

Ashkenazi Jewish (ASJ) AF: 0.204 AC: 5336 AN: 26102

East Asian (EAS) AF: 0.00550 AC: 218 AN: 39650

South Asian (SAS) AF: 0.139 AC: 11992 AN: 86042

European-Finnish (FIN) AF: 0.520 AC: 27675 AN: 53264

Middle Eastern (MID) AF: 0.164 AC: 945 AN: 5760

European-Non Finnish (NFE) AF: 0.361 AC: 401196 AN: 1110790

Other (OTH) AF: 0.280 AC: 16905 AN: 60282

GnomAD4 genome AF: 0.268 AC: 40741 AN: 152028 Hom.: 6889 Cov.: 32 AF XY: 0.272 AC XY: 20211 AN XY: 74314

African (AFR) AF: 0.123 AC: 5093 AN: 41458

American (AMR) AF: 0.231 AC: 3534 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.186 AC: 645 AN: 3468

East Asian (EAS) AF: 0.00771 AC: 40 AN: 5188

South Asian (SAS) AF: 0.125 AC: 602 AN: 4824

European-Finnish (FIN) AF: 0.537 AC: 5681 AN: 10582

Middle Eastern (MID) AF: 0.204 AC: 60 AN: 294

European-Non Finnish (NFE) AF: 0.357 AC: 24224 AN: 67920

Other (OTH) AF: 0.225 AC: 473 AN: 2102

Alfa AF: 0.316 Hom.: 8346

Bravo AF: 0.239

Asia WGS AF: 0.0840 AC: 293 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	1	Combined immunodeficiency due to ZAP70 deficiency (1)
-	-	1	not provided (2)
-	-	1	ZAP70-Related Severe Combined Immunodeficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	7.5
DANN	Benign	0.61
PhyloP100		-0.29
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: rs3192177; hg19: chr2-98354511; COSMIC: COSV53856101; COSMIC: COSV53856101;