NM_001079.4:c.531T>C

Variant names:

• chr2-97725220-T-C
• rs115846138
• NM_001079.4:c.531T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001079.4(ZAP70):​c.531T>C​(p.Leu177Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000646 in 1,613,912 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0033 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00037 (2 hom.)
• Consequence: ZAP70 NM_001079.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.192
• 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 2-97725220-T-C is Benign according to our data. Variant chr2-97725220-T-C is described in ClinVar as Benign. ClinVar VariationId is 471242.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.192 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00331 (504/152118) while in subpopulation AFR AF = 0.0115 (476/41516). AF 95% confidence interval is 0.0106. There are 2 homozygotes in GnomAd4. There are 234 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

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.531T>C	p.Leu177Leu	synonymous	Exon 4 of 14	NP_001070.2
	ZAP70	NM_001378594.1		c.531T>C	p.Leu177Leu	synonymous	Exon 3 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.531T>C	p.Leu177Leu	synonymous	Exon 4 of 14	ENSP00000264972.5	P43403-1
	ZAP70	ENST00000463643.5	TSL:1	n.392T>C		non_coding_transcript_exon	Exon 3 of 13
	ZAP70	ENST00000698508.2		c.531T>C	p.Leu177Leu	synonymous	Exon 3 of 13	ENSP00000513759.1	P43403-1

Frequencies

GnomAD3 genomes AF: 0.00330 AC: 502 AN: 152000 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0115

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00240

GnomAD2 exomes AF: 0.000844 AC: 212 AN: 251060 AF XY: 0.000575

Gnomad AFR exome AF: 0.0115

Gnomad AMR exome AF: 0.000550

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000369 AC: 539 AN: 1461794 Hom.: 2 Cov.: 33 AF XY: 0.000318 AC XY: 231 AN XY: 727182

African (AFR) AF: 0.0119 AC: 398 AN: 33480

American (AMR) AF: 0.000648 AC: 29 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.0000531 AC: 59 AN: 1111924

Other (OTH) AF: 0.000778 AC: 47 AN: 60394

GnomAD4 genome AF: 0.00331 AC: 504 AN: 152118 Hom.: 2 Cov.: 32 AF XY: 0.00315 AC XY: 234 AN XY: 74372

African (AFR) AF: 0.0115 AC: 476 AN: 41516

American (AMR) AF: 0.00124 AC: 19 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 67976

Other (OTH) AF: 0.00237 AC: 5 AN: 2106

Alfa AF: 0.00150 Hom.: 1

Bravo AF: 0.00377

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Combined immunodeficiency due to ZAP70 deficiency (2)
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	ZAP70-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	9.1
DANN	Benign	0.42
PhyloP100		0.19
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs115846138; hg19: chr2-98341683;