rs397514534
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PP5_Moderate
The NM_018706.7(DHTKD1):c.1228C>T(p.Arg410Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000867 in 1,613,952 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 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000089 ( 0 hom. )
Consequence
DHTKD1
NM_018706.7 stop_gained
NM_018706.7 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 5.96
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 10 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
?
Variant 10-12094141-C-T is Pathogenic according to our data. Variant chr10-12094141-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 39565.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DHTKD1 | NM_018706.7 | c.1228C>T | p.Arg410Ter | stop_gained | 7/17 | ENST00000263035.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DHTKD1 | ENST00000263035.9 | c.1228C>T | p.Arg410Ter | stop_gained | 7/17 | 1 | NM_018706.7 | P1 | |
DHTKD1 | ENST00000415935.1 | c.322C>T | p.Arg108Ter | stop_gained | 3/3 | 2 | |||
DHTKD1 | ENST00000465617.1 | n.368C>T | non_coding_transcript_exon_variant | 3/4 | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152096Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251490Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135920
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GnomAD4 exome AF: 0.00000889 AC: 13AN: 1461856Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7AN XY: 727228
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
2-aminoadipic 2-oxoadipic aciduria Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 06, 2023 | This sequence change creates a premature translational stop signal (p.Arg410*) 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). This variant is present in population databases (rs397514534, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with 2-aminoadipic and 2-oxoadipic aciduria (PMID: 23141293). ClinVar contains an entry for this variant (Variation ID: 39565). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 07, 2012 | - - |
Charcot-Marie-Tooth disease type 2A2 Uncertain:1
Uncertain significance, no assertion criteria provided | literature only | Inherited Neuropathy Consortium Ii, University Of Miami | Jan 06, 2016 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
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