11-118349850-G-A

Variant names:

• chr11-118349850-G-A
• rs755334490
• NM_000073.3:c.187G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_000073.3(CD3G):​c.187G>A​(p.Gly63Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,724 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G63G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: CD3G NM_000073.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: -0.868
• Publications: 3 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: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.034214348).
• BP6: Variant 11-118349850-G-A is Benign according to our data. Variant chr11-118349850-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 572829.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD3G	NM_000073.3	MANE Select	c.187G>A	p.Gly63Ser	missense	Exon 3 of 7	NP_000064.1	P09693
	CD3G	NM_001440319.1		c.187G>A	p.Gly63Ser	missense	Exon 3 of 7	NP_001427248.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD3G	ENST00000532917.3	TSL:1 MANE Select	c.187G>A	p.Gly63Ser	missense	Exon 3 of 7	ENSP00000431445.2	P09693
	CD3G	ENST00000528540.5	TSL:1	c.7G>A	p.Gly3Ser	missense	Exon 3 of 3	ENSP00000498162.1	A0A3B3IUD8
	CD3G	ENST00000292144.8	TSL:1	n.*244G>A		non_coding_transcript_exon	Exon 4 of 8	ENSP00000292144.4	J3KNA5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251406 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461724 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 727178

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000809 AC: 9 AN: 1111866

Other (OTH) AF: 0.0000166 AC: 1 AN: 60394

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	Combined immunodeficiency due to CD3gamma deficiency (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	0.018
DANN	Benign	0.41
DEOGEN2	Benign	0.13	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0032	N
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.034	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.64	N
PhyloP100		-0.87
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.039
Sift	Benign	0.75	T
Sift4G	Benign	0.25	T
Polyphen		0.0	B
Vest4		0.16
MVP		0.28
MPC		0.34
ClinPred		0.015	T
GERP RS		-5.4
Varity_R		0.13
gMVP		0.28
Mutation Taster		=91/9	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: rs755334490; hg19: chr11-118220565;