rs570768621

Positions:

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

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000073.3(CD3G):​c.213delA​(p.Lys71fs) 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:4
• Conservation: PhyloP100: -0.108

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]

ACMG classification

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 11-118349867-TA-T is Pathogenic according to our data. Variant chr11-118349867-TA-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 541654.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-118349867-TA-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CD3G	NM_000073.3	c.213delA	p.Lys71fs	frameshift_variant	3/7	ENST00000532917.3	NP_000064.1
CD3G	XM_005271724.5	c.213delA	p.Lys71fs	frameshift_variant	3/4		XP_005271781.1
CD3G	XM_006718941.4	c.213delA	p.Lys71fs	frameshift_variant	3/7		XP_006719004.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CD3G	ENST00000532917.3	c.213delA	p.Lys71fs	frameshift_variant	3/7	1	NM_000073.3	ENSP00000431445.2

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

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000228

Gnomad4 SAS exome AF: 0.0000349

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.0000618

Gnomad4 OTH exome AF: 0.0000501

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

Gnomad4 AFR AF: 0.0000243

Gnomad4 AMR AF: 0.0000659

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00117

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000887

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000217 Hom.: 0

Bravo AF: 0.0000793

EpiCase AF: 0.0000554

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Combined immunodeficiency due to CD3gamma deficiency Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 27, 2022	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 541654). This variant has not been reported in the literature in individuals affected with CD3G-related conditions. 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 sequence change creates a premature translational stop signal (p.Lys71Asnfs*40) 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). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 24, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 24, 2024	- -

Severe combined immunodeficiency disease Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Aug 08, 2022

Variant summary: CD3G c.213delA (p.Lys71AsnfsX40) 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. The variant allele was found at a frequency of 0.00011 in 246942 control chromosomes. This frequency is not higher than expected for a pathogenic variant in CD3G causing Severe Combined Immunodeficiency (0.00011 vs 0.00035). c.213delA has been reported in the literature in at-least one homozygous individual affected with Severe Combined Immunodeficiency whose T-B-NK+ SCID presentation was not supported by lymphocyte proliferation (example: Lee_2019). The authors reported a decrease in switched memory B cells and diminished CD40L expression with sufficient Treg suppression function. These data indicate that the variant may be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic, and as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs570768621; hg19: chr11-118220582;