rs3753059

Positions:

• chr11-118350634-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000073.3(CD3G):​c.390T>C​(p.Ala130Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.181 in 1,613,082 control chromosomes in the GnomAD database, including 33,340 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2879 hom., cov: 30)
  • Exomes 𝑓: 0.18 (30461 hom.)
• Consequence: CD3G NM_000073.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.937

Genes affected

CD3G (HGNC:1675): (CD3 gamma subunit of T-cell receptor complex) The protein encoded by this gene is the CD3-gamma polypeptide, which together with CD3-epsilon, -delta and -zeta, and the T-cell receptor alpha/beta and gamma/delta heterodimers, forms the T-cell receptor-CD3 complex. This complex plays an important role in coupling antigen recognition to several intracellular signal-transduction pathways. The genes encoding the epsilon, gamma and delta polypeptides are located in the same cluster on chromosome 11. Defects in this gene are associated with T cell immunodeficiency. [provided by RefSeq, Jul 2008]

CD3G (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 11-118350634-T-C is Benign according to our data. Variant chr11-118350634-T-C is described in ClinVar as [Benign]. Clinvar id is 302684.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-118350634-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.937 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.487 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CD3G	NM_000073.3	c.390T>C	p.Ala130Ala	synonymous_variant	4/7	ENST00000532917.3	NP_000064.1
CD3G	XM_005271724.5	c.390T>C	p.Ala130Ala	synonymous_variant	4/4		XP_005271781.1
CD3G	XM_006718941.4	c.390T>C	p.Ala130Ala	synonymous_variant	4/7		XP_006719004.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CD3G	ENST00000532917.3	c.390T>C	p.Ala130Ala	synonymous_variant	4/7	1	NM_000073.3	ENSP00000431445.2

Frequencies

GnomAD3 genomes AF: 0.177 AC: 26845 AN: 151532 Hom.: 2884 Cov.: 30

Gnomad AFR AF: 0.157

Gnomad AMI AF: 0.130

Gnomad AMR AF: 0.123

Gnomad ASJ AF: 0.231

Gnomad EAS AF: 0.503

Gnomad SAS AF: 0.466

Gnomad FIN AF: 0.186

Gnomad MID AF: 0.201

Gnomad NFE AF: 0.153

Gnomad OTH AF: 0.169

GnomAD3 exomes AF: 0.216 AC: 54245 AN: 251442 Hom.: 8098 AF XY: 0.230 AC XY: 31189 AN XY: 135882

Gnomad AFR exome AF: 0.157

Gnomad AMR exome AF: 0.0909

Gnomad ASJ exome AF: 0.232

Gnomad EAS exome AF: 0.502

Gnomad SAS exome AF: 0.455

Gnomad FIN exome AF: 0.186

Gnomad NFE exome AF: 0.156

Gnomad OTH exome AF: 0.201

GnomAD4 exome AF: 0.181 AC: 264617 AN: 1461432 Hom.: 30461 Cov.: 34 AF XY: 0.190 AC XY: 138154 AN XY: 727052

Gnomad4 AFR exome AF: 0.158

Gnomad4 AMR exome AF: 0.0962

Gnomad4 ASJ exome AF: 0.239

Gnomad4 EAS exome AF: 0.506

Gnomad4 SAS exome AF: 0.452

Gnomad4 FIN exome AF: 0.183

Gnomad4 NFE exome AF: 0.150

Gnomad4 OTH exome AF: 0.203

GnomAD4 genome AF: 0.177 AC: 26863 AN: 151650 Hom.: 2879 Cov.: 30 AF XY: 0.185 AC XY: 13740 AN XY: 74072

Gnomad4 AFR AF: 0.157

Gnomad4 AMR AF: 0.122

Gnomad4 ASJ AF: 0.231

Gnomad4 EAS AF: 0.503

Gnomad4 SAS AF: 0.465

Gnomad4 FIN AF: 0.186

Gnomad4 NFE AF: 0.154

Gnomad4 OTH AF: 0.173

Alfa AF: 0.150 Hom.: 1115

Bravo AF: 0.167

EpiCase AF: 0.166

EpiControl AF: 0.164

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Combined immunodeficiency due to CD3gamma deficiency Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 11, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 07, 2022	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: MAF -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	7.7
DANN	Benign	0.68

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

Publications

LitVar

Other links and lift over

dbSNP: rs3753059; hg19: chr11-118221349; COSMIC: COSV52676182; COSMIC: COSV52676182;