Variant 10-12069109-ACCGAGCGGGGCGTTTACGGCTACCGGCCGAGGAAGCCCGAGAGCCGCGAG-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1PP5

The NM_018706.7(DHTKD1):c.79_128del(p.Glu27ProfsTer10) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,610,776 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

DHTKD1
NM_018706.7 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 3.07

Variant links:

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]

DHTKD1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 34 pathogenic variants in the truncated region.

PP5

Variant 10-12069109-ACCGAGCGGGGCGTTTACGGCTACCGGCCGAGGAAGCCCGAGAGCCGCGAG-A is Pathogenic according to our data. Variant chr10-12069109-ACCGAGCGGGGCGTTTACGGCTACCGGCCGAGGAAGCCCGAGAGCCGCGAG-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2504734.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DHTKD1	NM_018706.7 linkuse as main transcript	c.79_128del	p.Glu27ProfsTer10	frameshift_variant	1/17	ENST00000263035.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DHTKD1	ENST00000263035.9 linkuse as main transcript	c.79_128del	p.Glu27ProfsTer10	frameshift_variant	1/17	1	NM_018706.7	P1
DHTKD1	ENST00000437298.1 linkuse as main transcript	c.79_128del	p.Glu27ProfsTer10	frameshift_variant	1/5	3

Frequencies

GnomAD3 genomes

AF:

0.0000921

AC:

AN:

152082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.00

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.0000167

AC:

AN:

239308

Hom.:

AF XY:

0.0000152

AC XY:

AN XY:

131208

show subpopulations

Gnomad AFR exome

AF:

0.000208

Gnomad AMR exome

AF:

0.0000294

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000548

AC:

AN:

1458694

Hom.:

AF XY:

0.00000551

AC XY:

AN XY:

725544

show subpopulations

Gnomad4 AFR exome

AF:

0.0000900

Gnomad4 AMR exome

AF:

0.0000449

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000499

GnomAD4 genome

AF:

0.0000921

AC:

AN:

152082

Hom.:

Cov.:

AF XY:

0.0000808

AC XY:

AN XY:

74298

show subpopulations

Gnomad4 AFR

AF:

0.000290

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.000169

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

2-aminoadipic 2-oxoadipic aciduria

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 21, 2023

This sequence change creates a premature translational stop signal (p.Glu27Profs*10) 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 (rs779758367, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with DHTKD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 2504734). For these reasons, this variant has been classified as Pathogenic. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 05, 2022

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over