rs747810875
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000108.5(DLD):āc.105C>Gā(p.Tyr35Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,612,508 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (ā ā ). Synonymous variant affecting the same amino acid position (i.e. Y35Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000108.5 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DLD | NM_000108.5 | c.105C>G | p.Tyr35Ter | stop_gained | 2/14 | ENST00000205402.10 | |
DLD | NM_001289751.1 | c.105C>G | p.Tyr35Ter | stop_gained | 2/13 | ||
DLD | NM_001289752.1 | c.105C>G | p.Tyr35Ter | stop_gained | 2/13 | ||
DLD | NM_001289750.1 | c.-44C>G | 5_prime_UTR_variant | 2/12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DLD | ENST00000205402.10 | c.105C>G | p.Tyr35Ter | stop_gained | 2/14 | 1 | NM_000108.5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152196Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1460312Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2AN XY: 726366
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152196Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74352
ClinVar
Submissions by phenotype
Pyruvate dehydrogenase E3 deficiency Pathogenic:4
Likely pathogenic, no assertion criteria provided | clinical testing | Counsyl | Jul 28, 2014 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 16, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 04, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 12, 2024 | This sequence change creates a premature translational stop signal (p.Tyr35*) in the DLD gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DLD are known to be pathogenic (PMID: 8968745, 9934985). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with dihydrolipoamide dehydrogenase deficiency (PMID: 8968745). ClinVar contains an entry for this variant (Variation ID: 421142). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 05, 2016 | The Y35X variant in the DLD gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The Y35X variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The Y35X variant is a strong candidate for a pathogenic variant; however, the possibility it may be a rare benign variant cannot be excluded. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at