NM_000073.3:c.158T>C

Variant names:

• chr11-118349821-T-C
• rs142915569
• NM_000073.3:c.158T>C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000073.3(CD3G):​c.158T>C​(p.Ile53Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00191 in 1,613,980 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0020 (3 hom.)
• Consequence: CD3G NM_000073.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 2.58

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008935899).
• BP6: Variant 11-118349821-T-C is Benign according to our data. Variant chr11-118349821-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 302681.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00143 (218/152118) while in subpopulation NFE AF= 0.00196 (133/68000). AF 95% confidence interval is 0.00168. There are 0 homozygotes in gnomad4. There are 89 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CD3G	NM_000073.3	c.158T>C	p.Ile53Thr	missense_variant	Exon 3 of 7	ENST00000532917.3	NP_000064.1
CD3G	XM_005271724.5	c.158T>C	p.Ile53Thr	missense_variant	Exon 3 of 4		XP_005271781.1
CD3G	XM_006718941.4	c.158T>C	p.Ile53Thr	missense_variant	Exon 3 of 7		XP_006719004.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CD3G	ENST00000532917.3	c.158T>C	p.Ile53Thr	missense_variant	Exon 3 of 7	1	NM_000073.3	ENSP00000431445.2

Frequencies

GnomAD3 genomes AF: 0.00143 AC: 218 AN: 152000 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00142

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00196

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00130 AC: 328 AN: 251432 Hom.: 2 AF XY: 0.00142 AC XY: 193 AN XY: 135886

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.00615

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00120

Gnomad NFE exome AF: 0.00164

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00196 AC: 2872 AN: 1461862 Hom.: 3 Cov.: 31 AF XY: 0.00192 AC XY: 1399 AN XY: 727236

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.00112

Gnomad4 ASJ exome AF: 0.00784

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00103

Gnomad4 NFE exome AF: 0.00219

Gnomad4 OTH exome AF: 0.00195

GnomAD4 genome AF: 0.00143 AC: 218 AN: 152118 Hom.: 0 Cov.: 31 AF XY: 0.00120 AC XY: 89 AN XY: 74356

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.00865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00142

Gnomad4 NFE AF: 0.00196

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00203 Hom.: 3

Bravo AF: 0.00157

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00209 AC: 18

ExAC AF: 0.00110 AC: 133

EpiCase AF: 0.00158

EpiControl AF: 0.00255

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Combined immunodeficiency due to CD3gamma deficiency Uncertain:1 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Nov 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CD3G-related disorder Benign:1

Sep 23, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Uncertain	0.70	D
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.077	N
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.0089	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Pathogenic	3.0	M
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.27
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.030	D
Polyphen		0.65	P
Vest4		0.47
MVP		0.76
MPC		0.71
ClinPred		0.058	T
GERP RS		4.8
Varity_R		0.49
gMVP		0.79

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: rs142915569; hg19: chr11-118220536;