11-118344456-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The ENST00000528540.5(CD3G):c.-131C>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000127 in 1,571,206 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00065 ( 2 hom., cov: 32)

Exomes 𝑓: 0.000071 ( 0 hom. )

Consequence

CD3G
ENST00000528540.5 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.215

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.021089911).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00065 (99/152344) while in subpopulation AFR AF = 0.00219 (91/41590). AF 95% confidence interval is 0.00182. There are 2 homozygotes in GnomAd4. There are 50 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CD3G	NM_000073.3 link	c.33C>G	p.Ile11Met	missense_variant	Exon 1 of 7	ENST00000532917.3	NP_000064.1	P09693B0YIY5
CD3G	NM_001440319.1 link	c.33C>G	p.Ile11Met	missense_variant	Exon 1 of 7
CD3G	XM_005271724.5 link	c.33C>G	p.Ile11Met	missense_variant	Exon 1 of 4		XP_005271781.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CD3G	ENST00000532917.3 link	c.33C>G	p.Ile11Met	missense_variant	Exon 1 of 7	1	NM_000073.3	ENSP00000431445.2		P09693

Frequencies

GnomAD3 genomes

AF:

0.000604

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00203

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000213

AC:

AN:

183168

AF XY:

0.000144

show subpopulations

Gnomad AFR exome

AF:

0.00169

Gnomad AMR exome

AF:

0.000486

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000781

Gnomad OTH exome

AF:

0.000205

GnomAD4 exome

AF:

0.0000712

AC:

101

AN:

1418862

Hom.:

Cov.:

AF XY:

0.0000556

AC XY:

AN XY:

701380

show subpopulations

African (AFR)

AF:

0.00110

AC:

AN:

32812

American (AMR)

AF:

0.000529

AC:

AN:

37788

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25296

East Asian (EAS)

AF:

0.00

AC:

AN:

37922

South Asian (SAS)

AF:

0.00

AC:

AN:

80462

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50594

Middle Eastern (MID)

AF:

0.000175

AC:

AN:

5710

European-Non Finnish (NFE)

AF:

0.0000239

AC:

AN:

1089480

Other (OTH)

AF:

0.000306

AC:

AN:

58798

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.436

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000650

AC:

AN:

152344

Hom.:

Cov.:

AF XY:

0.000671

AC XY:

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.00219

AC:

AN:

41590

American (AMR)

AF:

0.000327

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000169

Hom.:

Bravo

AF:

0.000744

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000151

AC:

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Combined immunodeficiency due to CD3gamma deficiency

Uncertain:1

Oct 13, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 11 of the CD3G protein (p.Ile11Met). This variant is present in population databases (rs143990986, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with CD3G-related conditions. ClinVar contains an entry for this variant (Variation ID: 580921). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Benign

0.63

DEOGEN2

Benign

0.34

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.68

M_CAP

Benign

0.047

MetaRNN

Benign

0.021

MetaSVM

Benign

-0.87

MutationAssessor

Uncertain

2.6

PhyloP100

0.21

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.7

REVEL

Benign

0.21

Sift

Uncertain

0.0030

Sift4G

Benign

0.11

Polyphen

0.93

Vest4

0.30

MVP

0.53

MPC

0.91

ClinPred

0.058

GERP RS

-0.24

PromoterAI

-0.021

Neutral

(source)

Varity_R

0.14

gMVP

0.40

Mutation Taster

=95/5

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

11-118344456-C-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over