rs199676861

Positions:

chr11-118349868-A-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000073.3(CD3G):c.205A>T(p.Lys69Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000493 in 1,583,362 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000050 ( 1 hom. )

Consequence

CD3G
NM_000073.3 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: -0.108

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 made for transcript

Verdict is Pathogenic. Variant got 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 11-118349868-A-T is Pathogenic according to our data. Variant chr11-118349868-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 100626.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-118349868-A-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CD3G	NM_000073.3 linkuse as main transcript	c.205A>T	p.Lys69Ter	stop_gained	3/7	ENST00000532917.3
CD3G	XM_005271724.5 linkuse as main transcript	c.205A>T	p.Lys69Ter	stop_gained	3/4
CD3G	XM_006718941.4 linkuse as main transcript	c.205A>T	p.Lys69Ter	stop_gained	3/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CD3G	ENST00000532917.3 linkuse as main transcript	c.205A>T	p.Lys69Ter	stop_gained	3/7	1	NM_000073.3	P1

Frequencies

GnomAD3 genomes

AF:

0.0000462

AC:

AN:

151400

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000289

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000191

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000590

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000729

AC:

AN:

247064

Hom.:

AF XY:

0.0000749

AC XY:

AN XY:

133584

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000552

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000380

Gnomad NFE exome

AF:

0.0000806

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000496

AC:

AN:

1431962

Hom.:

Cov.:

AF XY:

0.0000505

AC XY:

AN XY:

713552

show subpopulations

Gnomad4 AFR exome

AF:

0.0000609

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000256

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000247

Gnomad4 NFE exome

AF:

0.0000451

Gnomad4 OTH exome

AF:

0.000101

GnomAD4 genome

AF:

0.0000462

AC:

AN:

151400

Hom.:

Cov.:

AF XY:

0.0000271

AC XY:

AN XY:

73898

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000289

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000191

Gnomad4 NFE

AF:

0.0000590

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000847

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.0000828

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000180

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Combined immunodeficiency due to CD3gamma deficiency

Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 15, 2007	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 14, 2024	This sequence change creates a premature translational stop signal (p.Lys69*) 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). This variant is present in population databases (rs199676861, gnomAD 0.04%). This premature translational stop signal has been observed in individual(s) with clinical features of combined immunodeficiency (PMID: 17277165). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 100626). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 26, 2024	- -

not provided

Pathogenic:2

Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Uncertain

0.050

CADD

Benign

DANN

Benign

0.94

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.72

FATHMM_MKL

Benign

0.034

MutationTaster

Benign

1.0

A;A

Vest4

0.73

GERP RS

-2.1

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over