2-97739787-G-C

Variant names:

• chr2-97739787-G-C
• rs2278699
• NM_001079.4:c.*289G>C

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.*289G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.125 in 470,936 control chromosomes in the GnomAD database, including 4,247 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1828 hom., cov: 33)
  • Exomes 𝑓: 0.12 (2419 hom.)
• Consequence: ZAP70 NM_001079.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.349
• Publications: 10 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 2-97739787-G-C is Benign according to our data. Variant chr2-97739787-G-C is described in ClinVar as Benign. ClinVar VariationId is 337642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.222 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.*289G>C		3_prime_UTR	Exon 14 of 14	NP_001070.2
	ZAP70	NM_001378594.1		c.*289G>C		3_prime_UTR	Exon 13 of 13	NP_001365523.1	P43403-1
	ZAP70	NM_207519.2		c.*289G>C		3_prime_UTR	Exon 6 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.*289G>C		3_prime_UTR	Exon 14 of 14	ENSP00000264972.5	P43403-1
	ZAP70	ENST00000463643.5	TSL:1	n.2010G>C		non_coding_transcript_exon	Exon 13 of 13
	ZAP70	ENST00000698508.2		c.*289G>C		3_prime_UTR	Exon 13 of 13	ENSP00000513759.1	P43403-1

Frequencies

GnomAD3 genomes AF: 0.142 AC: 21611 AN: 152048 Hom.: 1826 Cov.: 33

Gnomad AFR AF: 0.226

Gnomad AMI AF: 0.212

Gnomad AMR AF: 0.102

Gnomad ASJ AF: 0.136

Gnomad EAS AF: 0.149

Gnomad SAS AF: 0.0948

Gnomad FIN AF: 0.0529

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.116

Gnomad OTH AF: 0.159

GnomAD4 exome AF: 0.116 AC: 37017 AN: 318770 Hom.: 2419 Cov.: 3 AF XY: 0.116 AC XY: 19122 AN XY: 165160

African (AFR) AF: 0.222 AC: 2173 AN: 9794

American (AMR) AF: 0.0932 AC: 1147 AN: 12310

Ashkenazi Jewish (ASJ) AF: 0.119 AC: 1259 AN: 10568

East Asian (EAS) AF: 0.145 AC: 3235 AN: 22386

South Asian (SAS) AF: 0.0991 AC: 2805 AN: 28310

European-Finnish (FIN) AF: 0.0615 AC: 1330 AN: 21618

Middle Eastern (MID) AF: 0.170 AC: 253 AN: 1492

European-Non Finnish (NFE) AF: 0.116 AC: 22402 AN: 192736

Other (OTH) AF: 0.123 AC: 2413 AN: 19556

GnomAD4 genome AF: 0.142 AC: 21620 AN: 152166 Hom.: 1828 Cov.: 33 AF XY: 0.139 AC XY: 10307 AN XY: 74406

African (AFR) AF: 0.226 AC: 9378 AN: 41482

American (AMR) AF: 0.102 AC: 1558 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.136 AC: 471 AN: 3470

East Asian (EAS) AF: 0.148 AC: 767 AN: 5176

South Asian (SAS) AF: 0.0949 AC: 458 AN: 4826

European-Finnish (FIN) AF: 0.0529 AC: 562 AN: 10614

Middle Eastern (MID) AF: 0.167 AC: 49 AN: 294

European-Non Finnish (NFE) AF: 0.115 AC: 7852 AN: 67984

Other (OTH) AF: 0.157 AC: 332 AN: 2114

Alfa AF: 0.128 Hom.: 195

Bravo AF: 0.153

Asia WGS AF: 0.0970 AC: 336 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.94
DANN	Benign	0.72
PhyloP100		-0.35
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: rs2278699; hg19: chr2-98356250;