rs570768621

Variant names:

• chr11-118349867-TA-T
• rs570768621
• NM_000073.3:c.213delA

Your query was ambiguous. Multiple possible variants found:

• chr11-118349867-TA-T
• chr11-118349867-TA-TAA
• chr11-118349867-TA-TAAA

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000073.3(CD3G):​c.213delA​(p.Lys71AsnfsTer40) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000619 in 1,599,382 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 0.000093 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000059 (0 hom.)
• Consequence: CD3G NM_000073.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: -0.108
• Publications: 13 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 11-118349867-TA-T is Pathogenic according to our data. Variant chr11-118349867-TA-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 541654.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.213delA	p.Lys71AsnfsTer40	frameshift	Exon 3 of 7	NP_000064.1	P09693
	CD3G	NM_001440319.1		c.213delA	p.Lys71AsnfsTer40	frameshift	Exon 3 of 7	NP_001427248.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD3G	ENST00000532917.3	TSL:1 MANE Select	c.213delA	p.Lys71AsnfsTer40	frameshift	Exon 3 of 7	ENSP00000431445.2	P09693
	CD3G	ENST00000528540.5	TSL:1	c.33delA	p.Lys11fs	frameshift splice_region	Exon 3 of 3	ENSP00000498162.1	A0A3B3IUD8
	CD3G	ENST00000292144.8	TSL:1	n.*270delA		non_coding_transcript_exon	Exon 4 of 8	ENSP00000292144.4	J3KNA5

Frequencies

GnomAD3 genomes AF: 0.0000862 AC: 13 AN: 150794 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000244

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000660

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00117

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000739

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000105 AC: 26 AN: 246942 AF XY: 0.000135

Gnomad AFR exome AF: 0.0000624

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000663

Gnomad FIN exome AF: 0.0000471

Gnomad NFE exome AF: 0.0000985

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000587 AC: 85 AN: 1448482 Hom.: 0 Cov.: 32 AF XY: 0.0000555 AC XY: 40 AN XY: 721166

African (AFR) AF: 0.00 AC: 0 AN: 33184

American (AMR) AF: 0.00 AC: 0 AN: 44574

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25912

East Asian (EAS) AF: 0.000228 AC: 9 AN: 39400

South Asian (SAS) AF: 0.0000349 AC: 3 AN: 86006

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53088

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5724

European-Non Finnish (NFE) AF: 0.0000618 AC: 68 AN: 1100768

Other (OTH) AF: 0.0000501 AC: 3 AN: 59826

GnomAD4 genome AF: 0.0000928 AC: 14 AN: 150900 Hom.: 0 Cov.: 31 AF XY: 0.000109 AC XY: 8 AN XY: 73676

African (AFR) AF: 0.0000243 AC: 1 AN: 41112

American (AMR) AF: 0.0000659 AC: 1 AN: 15166

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00117 AC: 6 AN: 5136

South Asian (SAS) AF: 0.00 AC: 0 AN: 4750

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10328

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000887 AC: 6 AN: 67644

Other (OTH) AF: 0.00 AC: 0 AN: 2102

Alfa AF: 0.000217 Hom.: 0

Bravo AF: 0.0000793

EpiCase AF: 0.0000554

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Combined immunodeficiency due to CD3gamma deficiency (2)
1	-	-	Severe combined immunodeficiency disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.11
Mutation Taster		=4/196	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs570768621; hg19: chr11-118220582; COSMIC: COSV52673575;