Genetic Variant NM_000073.3:c.205A>T (chr11-118349868-A-T) – 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.205A>T(p.Lys69*) 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:6

Conservation

PhyloP100: -0.108

Publications

9 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: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet

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 11-118349868-A-T is Pathogenic according to our data. Variant chr11-118349868-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 100626.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.205A>T	p.Lys69*	stop_gained	Exon 3 of 7	NP_000064.1	P09693
	CD3G	NM_001440319.1		c.205A>T	p.Lys69*	stop_gained	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.205A>T	p.Lys69*	stop_gained	Exon 3 of 7	ENSP00000431445.2	P09693
CD3G	ENST00000528540.5	TSL:1	c.25A>T	p.Lys9*	stop_gained	Exon 3 of 3	ENSP00000498162.1	A0A3B3IUD8
CD3G	ENST00000292144.8	TSL:1	n.*262A>T		non_coding_transcript_exon	Exon 4 of 8	ENSP00000292144.4	J3KNA5

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

GnomAD2 exomes

AF:

0.0000729

AC:

AN:

247064

AF XY:

0.0000749

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 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

African (AFR)

AF:

0.0000609

AC:

AN:

32830

American (AMR)

AF:

0.00

AC:

AN:

44396

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25692

East Asian (EAS)

AF:

0.0000256

AC:

AN:

39064

South Asian (SAS)

AF:

0.00

AC:

AN:

85594

European-Finnish (FIN)

AF:

0.000247

AC:

AN:

52714

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5678

European-Non Finnish (NFE)

AF:

0.0000451

AC:

AN:

1086802

Other (OTH)

AF:

0.000101

AC:

AN:

59192

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.0000462

AC:

AN:

151400

Hom.:

Cov.:

AF XY:

0.0000271

AC XY:

AN XY:

73898

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41206

American (AMR)

AF:

0.00

AC:

AN:

15174

Ashkenazi Jewish (ASJ)

AF:

0.000289

AC:

AN:

3460

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4784

European-Finnish (FIN)

AF:

0.000191

AC:

AN:

10478

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000590

AC:

AN:

67818

Other (OTH)

AF:

0.00

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.532

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:

0.0000847

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.0000828

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000180

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Combined immunodeficiency due to CD3gamma deficiency (4)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Uncertain

0.050

CADD

Benign

(source)

DANN

Benign

0.94

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.72

FATHMM_MKL

Benign

0.034

PhyloP100

-0.11

Vest4

0.73

GERP RS

-2.1

Mutation Taster

=1/199

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