Genetic Variant CD3G:p.Trp72MetfsTer6 (chr11-118349867-T-TA) – ACMG Classification: Pathogenic (18 pts)

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:3

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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 580586.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.213dupA	p.Trp72MetfsTer6	frameshift	Exon 3 of 7	NP_000064.1	P09693
	CD3G	NM_001440319.1		c.213dupA	p.Trp72MetfsTer6	frameshift	Exon 3 of 7	NP_001427248.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CD3G	ENST00000532917.3	TSL:1 MANE Select	c.213dupA	p.Trp72MetfsTer6	frameshift	Exon 3 of 7	ENSP00000431445.2	P09693
CD3G	ENST00000292144.8	TSL:1	n.*270dupA		non_coding_transcript_exon	Exon 4 of 8	ENSP00000292144.4	J3KNA5
CD3G	ENST00000292144.8	TSL:1	n.*270dupA		3_prime_UTR	Exon 4 of 8	ENSP00000292144.4	J3KNA5

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

ClinVar submissions as Germline

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Combined immunodeficiency due to CD3gamma deficiency (2)

Severe combined immunodeficiency disease (1)

Computational scores

Source: dbNSFP v4.9

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over