chr11-118339445-G-A

Variant names:

• chr11-118339445-G-A
• rs193922617
• NM_000732.6:c.450+6C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_000732.6(CD3D):​c.450+6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000075 in 1,613,576 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000070 (0 hom.)
• Consequence: CD3D NM_000732.6 splice_region, intron
• Scores: Splicing: ADA: 0.000008654
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: -0.0410
• Publications: 0 publications found

Genes affected

CD3D (HGNC:1673): (CD3 delta subunit of T-cell receptor complex) The protein encoded by this gene is part of the T-cell receptor/CD3 complex (TCR/CD3 complex) and is involved in T-cell development and signal transduction. The encoded membrane protein represents the delta subunit of the CD3 complex, and along with four other CD3 subunits, binds either TCR alpha/beta or TCR gamma/delta to form the TCR/CD3 complex on the surface of T-cells. Defects in this gene are a cause of severe combined immunodeficiency autosomal recessive T-cell-negative/B-cell-positive/NK-cell-positive (SCIDBNK). Two transcript variants encoding different isoforms have been found for this gene. Other variants may also exist, but the full-length natures of their transcripts has yet to be defined. [provided by RefSeq, Feb 2009]

CD3D Gene-Disease associations (from GenCC):

• immunodeficiency 19

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
• T-B+ severe combined immunodeficiency due to CD3delta/CD3epsilon/CD3zeta

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000119 (18/151840) while in subpopulation AMR AF = 0.000985 (15/15230). AF 95% confidence interval is 0.000606. There are 0 homozygotes in GnomAd4. There are 11 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CD3D	NM_000732.6	c.450+6C>T		splice_region_variant, intron_variant	Intron 4 of 4	ENST00000300692.9	NP_000723.1
CD3D	NM_001040651.2	c.318+6C>T		splice_region_variant, intron_variant	Intron 3 of 3		NP_001035741.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CD3D	ENST00000300692.9	c.450+6C>T		splice_region_variant, intron_variant	Intron 4 of 4	1	NM_000732.6	ENSP00000300692.4

Frequencies

GnomAD3 genomes AF: 0.000119 AC: 18 AN: 151840 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000985

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000183 AC: 46 AN: 251472 AF XY: 0.000177

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000705 AC: 103 AN: 1461736 Hom.: 0 Cov.: 33 AF XY: 0.0000633 AC XY: 46 AN XY: 727184

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00154 AC: 69 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000270 AC: 30 AN: 1111876

Other (OTH) AF: 0.0000166 AC: 1 AN: 60390

GnomAD4 genome AF: 0.000119 AC: 18 AN: 151840 Hom.: 0 Cov.: 31 AF XY: 0.000148 AC XY: 11 AN XY: 74132

African (AFR) AF: 0.0000242 AC: 1 AN: 41316

American (AMR) AF: 0.000985 AC: 15 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10570

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67962

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.000134 Hom.: 0

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Immunodeficiency 19 Uncertain:2

Sep 01, 2022

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in the literature but is present in the Genome Aggregation Database (Highest reported MAF 0.1% (15/15230) (https://gnomad.broadinstitute.org/variant/11-118339445-G-A?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID:35805). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant is an intronic variant with no predicted change in the amino acid sequence but may have an unknown effect on splicing. Splice prediction tools do not suggest that this variant may affect splicing. However, further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Sep 27, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 4 of the CD3D gene. It does not directly change the encoded amino acid sequence of the CD3D protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs193922617, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with CD3D-related conditions. ClinVar contains an entry for this variant (Variation ID: 35805). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Severe combined immunodeficiency disease Uncertain:1

Aug 18, 2011

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing;curation

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	7.2
DANN	Benign	0.82
PhyloP100		-0.041
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000087
dbscSNV1_RF	Benign	0.028
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: rs193922617; hg19: chr11-118210160;