rs193922617
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Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting
The NM_000732.6(CD3D):c.450+6C>T variant causes a splice donor 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. 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_donor_region, intron
NM_000732.6 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.000008654
2
Clinical Significance
Conservation
PhyloP100: -0.0410
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -3 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
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 male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CD3D | NM_000732.6 | c.450+6C>T | splice_donor_region_variant, intron_variant | ENST00000300692.9 | |||
CD3D | NM_001040651.2 | c.318+6C>T | splice_donor_region_variant, intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CD3D | ENST00000300692.9 | c.450+6C>T | splice_donor_region_variant, intron_variant | 1 | NM_000732.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000119 AC: 18AN: 151840Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.000183 AC: 46AN: 251472Hom.: 0 AF XY: 0.000177 AC XY: 24AN XY: 135908
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GnomAD4 exome AF: 0.0000705 AC: 103AN: 1461736Hom.: 0 Cov.: 33 AF XY: 0.0000633 AC XY: 46AN XY: 727184
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Immunodeficiency 19 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 27, 2022 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Sep 01, 2022 | 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. - |
Severe combined immunodeficiency disease Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing;curation | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 18, 2011 | - - |
Computational scores
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at