11-118349821-T-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000073.3(CD3G):​c.158T>G​(p.Ile53Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I53T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CD3G NM_000073.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.58
• Publications: 7 publications found

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 Gene-Disease associations (from GenCC):

• combined immunodeficiency due to CD3gamma deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.791

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000073.3. 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
	CD3G	NM_000073.3	MANE Select	c.158T>G	p.Ile53Ser	missense	Exon 3 of 7	NP_000064.1
	CD3G	NM_001440319.1		c.158T>G	p.Ile53Ser	missense	Exon 3 of 7	NP_001427248.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD3G	ENST00000532917.3	TSL:1 MANE Select	c.158T>G	p.Ile53Ser	missense	Exon 3 of 7	ENSP00000431445.2
	CD3G	ENST00000292144.8	TSL:1	n.*215T>G		non_coding_transcript_exon	Exon 4 of 8	ENSP00000292144.4
	CD3G	ENST00000528540.5	TSL:1	c.-23T>G		5_prime_UTR	Exon 3 of 3	ENSP00000498162.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000795 AC: 2 AN: 251432 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461862 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727236

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111990

Other (OTH) AF: 0.00 AC: 0 AN: 60396

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0296732), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 3

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.099	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.74	D
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.44	T
M_CAP	Benign	0.030	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Benign	-0.83	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		2.6
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-4.0	D
REVEL	Benign	0.25
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.023	D
Polyphen		0.65	P
Vest4		0.59
MutPred		0.65		Gain of disorder (P = 0.0318)
MVP		0.67
MPC		0.79
ClinPred		0.76	D
GERP RS		4.8
Varity_R		0.85
gMVP		0.93
Mutation Taster		=80/20	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: rs142915569; hg19: chr11-118220536;