10-12094222-G-T

Position:

chr10-12094222-G-T

Variant summary

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

The NM_018706.7(DHTKD1):c.1309G>T(p.Glu437Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000103 in 1,614,026 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 Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

DHTKD1
NM_018706.7 stop_gained

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U:1

Conservation

PhyloP100: 9.83

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 10-12094222-G-T is Pathogenic according to our data. Variant chr10-12094222-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 574714.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=1, Pathogenic=4}. Variant chr10-12094222-G-T is described in Lovd as [Pathogenic]. Variant chr10-12094222-G-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DHTKD1	NM_018706.7 linkuse as main transcript	c.1309G>T	p.Glu437Ter	stop_gained	7/17	ENST00000263035.9	NP_061176.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
DHTKD1	ENST00000263035.9 linkuse as main transcript	c.1309G>T	p.Glu437Ter	stop_gained	7/17	1	NM_018706.7	ENSP00000263035	P1
DHTKD1	ENST00000415935.1 linkuse as main transcript	c.403G>T	p.Glu135Ter	stop_gained	3/3	2		ENSP00000400625
DHTKD1	ENST00000465617.1 linkuse as main transcript	n.449G>T		non_coding_transcript_exon_variant	3/4	3
DHTKD1	ENST00000448829.1 linkuse as main transcript			upstream_gene_variant		5		ENSP00000398482

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000191

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000596

AC:

AN:

251488

Hom.:

AF XY:

0.0000515

AC XY:

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.000132

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000104

AC:

152

AN:

1461888

Hom.:

Cov.:

AF XY:

0.000100

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.000132

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000920

AC:

AN:

152138

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000132

Hom.:

Bravo

AF:

0.000113

ExAC

AF:

0.0000741

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

2-aminoadipic 2-oxoadipic aciduria

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 14, 2023	Variant summary: DHTKD1 c.1309G>T (p.Glu437X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic in ClinVar and associated with 2-Aminoadipic 2-Oxoadipic Aciduria in HGMD. The variant allele was found at a frequency of 6e-05 in 251488 control chromosomes. c.1309G>T has been reported in the literature in individuals affected with 2-Aminoadipic 2-Oxoadipic Aciduria (Hagen_2015) as well as in Charcot-Marie-Tooth Type 2Q (Dohrn_2017) and Amyotrophic Lateral Sclerosis (Osmanovic_2022). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, classifying the variant as pathogenic (n=3), likely pathogenic (n=2), uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	May 31, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 07, 2023	This sequence change creates a premature translational stop signal (p.Glu437*) 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 (rs138884194, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with alpha-aminoadipic and alpha-ketoadipic aciduria (PMID: 25860818). ClinVar contains an entry for this variant (Variation ID: 574714). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Nov 30, 2020	This sequence change creates a premature termination codon at position 437 in exon 7 (of 17) of DHTKD1 (p.Glu437*). 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 - PVS1). The variant is present in a large population cohort at a frequency of 0.006% (rs138884194, 18/282,894 alleles in gnomAD v2.1 - PM2). It has been reported compound heterozygous with a second pathogenic variant in a case diagnosed with alpha-aminoadipic and alpha-ketoadipic aciduria (PMID: 25860818 - PM3). Based on the classification scheme RMH ACMG Guidelines v1.1.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PM2, PM3. -

not provided

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2022	DHTKD1: PVS1:Moderate -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 21, 2019	- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 15, 2022

The c.1309G>T (p.E437*) alteration, located in exon 7 (coding exon 7) of the DHTKD1 gene, consists of a G to T substitution at nucleotide position 1309. This changes the amino acid from a glutamic acid (E) to a stop codon at amino acid position 437. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This alteration co-occurred with a second alteration in the DHTKD1 gene in an individual with alpha-aminoadipic and alpha-ketoadipic aciduria; however, information of the phase of these alterations was not provided (Hagen, 2015). Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.66

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.98

FATHMM_MKL

Pathogenic

0.99

MutationTaster

Benign

1.0

Vest4

0.41

GERP RS

4.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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