chr10-12107995-C-T
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Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_018706.7(DHTKD1):c.2134C>T(p.Arg712Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000229 in 1,613,454 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000021 ( 0 hom. )
Consequence
DHTKD1
NM_018706.7 stop_gained
NM_018706.7 stop_gained
Scores
3
3
1
Clinical Significance
Conservation
PhyloP100: 4.24
Genes affected
DHTKD1 (HGNC:23537): (dehydrogenase E1 and transketolase domain containing 1) This gene encodes a component of a mitochondrial 2-oxoglutarate-dehydrogenase-complex-like protein involved in the degradation pathways of several amino acids, including lysine. Mutations in this gene are associated with 2-aminoadipic 2-oxoadipic aciduria and Charcot-Marie-Tooth Disease Type 2Q. [provided by RefSeq, May 2013]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 10-12107995-C-T is Pathogenic according to our data. Variant chr10-12107995-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 572241.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DHTKD1 | NM_018706.7 | c.2134C>T | p.Arg712Ter | stop_gained | 12/17 | ENST00000263035.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DHTKD1 | ENST00000263035.9 | c.2134C>T | p.Arg712Ter | stop_gained | 12/17 | 1 | NM_018706.7 | P1 | |
DHTKD1 | ENST00000448829.1 | c.639C>T | p.Val213= | synonymous_variant | 5/6 | 5 |
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152118Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251172Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135734
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GnomAD4 exome AF: 0.0000205 AC: 30AN: 1461336Hom.: 0 Cov.: 32 AF XY: 0.0000179 AC XY: 13AN XY: 726996
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GnomAD4 genome AF: 0.0000460 AC: 7AN: 152118Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74290
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 30, 2022 | - - |
2-aminoadipic 2-oxoadipic aciduria Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 05, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 572241). This premature translational stop signal has been observed in individual(s) with alpha-ketoadipic aciduria (PMID: 25860818). This variant is present in population databases (rs745432268, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Arg712*) in the DHTKD1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DHTKD1 are known to be pathogenic (PMID: 23141293, 25860818). - |
Computational scores
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Name
Calibrated prediction
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BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at