rs200788729

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PS1_ModeratePM5PP3_StrongPP5_Moderate

The NM_018706.7(DHTKD1):c.2143C>T(p.Arg715Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000242 in 1,612,732 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 (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R715H) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

DHTKD1
NM_018706.7 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 4.21

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 Pathogenic. Variant got 10 ACMG points.

PS1

Transcript NM_018706.7 (DHTKD1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt

PM5

Other missense variant is known to change same aminoacid residue: Variant chr10-12108005-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3065235.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.961

PP5

Variant 10-12108004-C-T is Pathogenic according to our data. Variant chr10-12108004-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 242503.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 linkuse as main transcript	c.2143C>T	p.Arg715Cys	missense_variant	12/17	ENST00000263035.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DHTKD1	ENST00000263035.9 linkuse as main transcript	c.2143C>T	p.Arg715Cys	missense_variant	12/17	1	NM_018706.7	P1
DHTKD1	ENST00000448829.1 linkuse as main transcript	c.*3C>T		3_prime_UTR_variant	5/6	5

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

250894

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135608

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000240

AC:

AN:

1460480

Hom.:

Cov.:

AF XY:

0.0000261

AC XY:

AN XY:

726596

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000270

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152252

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000579

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 01, 2023

The c.2143C>T (p.R715C) alteration is located in exon 12 (coding exon 12) of the DHTKD1 gene. This alteration results from a C to T substitution at nucleotide position 2143, causing the arginine (R) at amino acid position 715 to be replaced by a cysteine (C). Based on data from gnomAD, the T allele has an overall frequency of 0.003% (7/282290) total alleles studied. The highest observed frequency was 0.02% (4/19934) of East Asian alleles. This alteration was detected in conjunction with another alteration in DHTKD1 in an individual with clinical features of Alpha-aminoadipic and alpha-ketoadipic aciduria (Stiles, 2016). In vitro functional studies indicate this alteration leads to diminished protein activity (Nemeria, 2022). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.86

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.47

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Uncertain

0.60

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.49

MetaRNN

Pathogenic

0.96

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.6

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-7.5

REVEL

Pathogenic

0.86

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.97

MVP

0.86

MPC

0.64

ClinPred

1.0

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.96

gMVP

0.90

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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