chr11-118349867-T-TA

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000073.3(CD3G):c.213dupA(p.Trp72MetfsTer6) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000862 in 1,601,060 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000092 ( 0 hom. )

Consequence

CD3G
NM_000073.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: -0.108

Publications

13 publications found

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 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

CD3G links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-118349867-T-TA is Pathogenic according to our data. Variant chr11-118349867-T-TA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 580586.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CD3G	NM_000073.3 link	c.213dupA	p.Trp72MetfsTer6	frameshift_variant	Exon 3 of 7	ENST00000532917.3	NP_000064.1	P09693B0YIY5
CD3G	NM_001440319.1 link	c.213dupA	p.Trp72MetfsTer6	frameshift_variant	Exon 3 of 7		NP_001427248.1
CD3G	XM_005271724.5 link	c.213dupA	p.Trp72MetfsTer6	frameshift_variant	Exon 3 of 4		XP_005271781.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CD3G	ENST00000532917.3 link	c.213dupA	p.Trp72MetfsTer6	frameshift_variant	Exon 3 of 7	1	NM_000073.3	ENSP00000431445.2		P09693

Frequencies

GnomAD3 genomes

AF:

0.0000265

AC:

AN:

150804

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000591

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000526

AC:

AN:

246942

AF XY:

0.0000674

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000295

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000553

Gnomad FIN exome

AF:

0.0000471

Gnomad NFE exome

AF:

0.0000716

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000924

AC:

134

AN:

1450256

Hom.:

Cov.:

AF XY:

0.0000914

AC XY:

AN XY:

721972

show subpopulations

African (AFR)

AF:

0.0000601

AC:

AN:

33252

American (AMR)

AF:

0.0000224

AC:

AN:

44602

Ashkenazi Jewish (ASJ)

AF:

0.0000386

AC:

AN:

25922

East Asian (EAS)

AF:

0.0000507

AC:

AN:

39450

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86052

European-Finnish (FIN)

AF:

0.0000564

AC:

AN:

53150

Middle Eastern (MID)

AF:

0.000349

AC:

AN:

5728

European-Non Finnish (NFE)

AF:

0.000103

AC:

114

AN:

1102182

Other (OTH)

AF:

0.000117

AC:

AN:

59918

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

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000265

AC:

AN:

150804

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73562

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41000

American (AMR)

AF:

0.00

AC:

AN:

15150

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3460

East Asian (EAS)

AF:

0.00

AC:

AN:

5148

South Asian (SAS)

AF:

0.00

AC:

AN:

4754

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10332

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000591

AC:

AN:

67656

Other (OTH)

AF:

0.00

AC:

AN:

2078

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Combined immunodeficiency due to CD3gamma deficiency

Pathogenic:1

Dec 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Trp72Metfs*6) in the CD3G gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CD3G are known to be pathogenic (PMID: 1635567, 17277165, 24910257). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 580586). For these reasons, this variant has been classified as Pathogenic. -

Severe combined immunodeficiency disease

Pathogenic:1

Jun 24, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: CD3G c.213dupA (p.Trp72MetfsX6) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic within ClinVar (e.g. c.496C>T [p.Arg166Ter]). The variant allele was found at a frequency of 5.3e-05 in 246942 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in CD3G causing Severe Combined Immunodeficiency (5.3e-05 vs 0.00035), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.213dupA in individuals affected with Severe Combined Immunodeficiency and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submitters have assessed the variant since 2014: both classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.11

Mutation Taster

=6/194

disease causing (ClinVar)

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over