rs56127120

Variant names:

• chr2-97724141-G-A
• rs56127120
• NM_001079.4:c.105G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-97724141-G-A
• chr2-97724141-G-C

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.105G>A​(p.Leu35Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00371 in 1,569,446 control chromosomes in the GnomAD database, including 172 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L35L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0045 (17 hom., cov: 33)
  • Exomes 𝑓: 0.0036 (155 hom.)
• Consequence: ZAP70 NM_001079.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.20
• Publications: 1 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=-0.49).
• BP6: Variant 2-97724141-G-A is Benign according to our data. Variant chr2-97724141-G-A is described in ClinVar as Benign. ClinVar VariationId is 337626.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=3.2 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0616 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZAP70	NM_001079.4	MANE Select	c.105G>A	p.Leu35Leu	synonymous	Exon 3 of 14	NP_001070.2
	ZAP70	NM_001378594.1		c.105G>A	p.Leu35Leu	synonymous	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.105G>A	p.Leu35Leu	synonymous	Exon 3 of 14	ENSP00000264972.5
	ZAP70	ENST00000698508.2		c.105G>A	p.Leu35Leu	synonymous	Exon 2 of 13	ENSP00000513759.1
	ZAP70	ENST00000885386.1		c.105G>A	p.Leu35Leu	synonymous	Exon 3 of 14	ENSP00000555445.1

Frequencies

GnomAD3 genomes AF: 0.00449 AC: 683 AN: 152254 Hom.: 17 Cov.: 33

Gnomad AFR AF: 0.00142

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000392

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0672

Gnomad SAS AF: 0.00744

Gnomad FIN AF: 0.0144

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00103

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00671 AC: 1251 AN: 186372 AF XY: 0.00611

Gnomad AFR exome AF: 0.00147

Gnomad AMR exome AF: 0.000169

Gnomad ASJ exome AF: 0.000111

Gnomad EAS exome AF: 0.0598

Gnomad FIN exome AF: 0.0146

Gnomad NFE exome AF: 0.00106

Gnomad OTH exome AF: 0.00780

GnomAD4 exome AF: 0.00363 AC: 5142 AN: 1417074 Hom.: 155 Cov.: 32 AF XY: 0.00357 AC XY: 2507 AN XY: 701430

African (AFR) AF: 0.000765 AC: 25 AN: 32678

American (AMR) AF: 0.000173 AC: 7 AN: 40494

Ashkenazi Jewish (ASJ) AF: 0.000118 AC: 3 AN: 25486

East Asian (EAS) AF: 0.0842 AC: 3153 AN: 37464

South Asian (SAS) AF: 0.00402 AC: 331 AN: 82240

European-Finnish (FIN) AF: 0.0133 AC: 570 AN: 42968

Middle Eastern (MID) AF: 0.000364 AC: 2 AN: 5500

European-Non Finnish (NFE) AF: 0.000614 AC: 670 AN: 1091634

Other (OTH) AF: 0.00650 AC: 381 AN: 58610

GnomAD4 genome AF: 0.00450 AC: 685 AN: 152372 Hom.: 17 Cov.: 33 AF XY: 0.00543 AC XY: 405 AN XY: 74518

African (AFR) AF: 0.00142 AC: 59 AN: 41592

American (AMR) AF: 0.000392 AC: 6 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.0674 AC: 349 AN: 5180

South Asian (SAS) AF: 0.00745 AC: 36 AN: 4834

European-Finnish (FIN) AF: 0.0144 AC: 153 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00103 AC: 70 AN: 68034

Other (OTH) AF: 0.00520 AC: 11 AN: 2116

Alfa AF: 0.00159 Hom.: 1

Bravo AF: 0.00263

Asia WGS AF: 0.0500 AC: 173 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	8.5
DANN	Benign	0.77
PhyloP100		3.2
Mutation Taster		=100/0	polymorphism

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: rs56127120; hg19: chr2-98340604; COSMIC: COSV53858413; COSMIC: COSV53858413;