10-12069091-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_018706.7(DHTKD1):c.58T>C(p.Phe20Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.994 in 1,612,620 control chromosomes in the GnomAD database, including 797,667 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.97 (71792 hom., cov: 35)
  • Exomes 𝑓: 1.0 (725875 hom.)
• Consequence: DHTKD1 NM_018706.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.834

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.919831E-7).
• BP6: Variant 10-12069091-T-C is Benign according to our data. Variant chr10-12069091-T-C is described in ClinVar as [Benign]. Clinvar id is 1168371.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-12069091-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DHTKD1	NM_018706.7	c.58T>C	p.Phe20Leu	missense_variant	1/17	ENST00000263035.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DHTKD1	ENST00000263035.9	c.58T>C	p.Phe20Leu	missense_variant	1/17	1	NM_018706.7	P1
DHTKD1	ENST00000437298.1	c.58T>C	p.Phe20Leu	missense_variant	1/5	3

Frequencies

GnomAD3 genomes AF: 0.970 AC: 147589 AN: 152210 Hom.: 71740 Cov.: 35

Gnomad AFR AF: 0.894

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.989

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 0.999

Gnomad MID AF: 0.994

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.979

GnomAD3 exomes AF: 0.992 AC: 242883 AN: 244766 Hom.: 120592 AF XY: 0.994 AC XY: 132939 AN XY: 133716

Gnomad AFR exome AF: 0.894

Gnomad AMR exome AF: 0.994

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 1.00

Gnomad FIN exome AF: 0.998

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.997

GnomAD4 exome AF: 0.997 AC: 1455841 AN: 1460292 Hom.: 725875 Cov.: 61 AF XY: 0.997 AC XY: 724553 AN XY: 726448

Gnomad4 AFR exome AF: 0.895

Gnomad4 AMR exome AF: 0.994

Gnomad4 ASJ exome AF: 1.00

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 1.00

Gnomad4 FIN exome AF: 0.999

Gnomad4 NFE exome AF: 1.00

Gnomad4 OTH exome AF: 0.994

GnomAD4 genome AF: 0.970 AC: 147700 AN: 152328 Hom.: 71792 Cov.: 35 AF XY: 0.972 AC XY: 72373 AN XY: 74492

Gnomad4 AFR AF: 0.895

Gnomad4 AMR AF: 0.989

Gnomad4 ASJ AF: 1.00

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 1.00

Gnomad4 FIN AF: 0.999

Gnomad4 NFE AF: 1.00

Gnomad4 OTH AF: 0.980

Alfa AF: 0.988 Hom.: 39433

Bravo AF: 0.966

TwinsUK AF: 1.00 AC: 3708

ALSPAC AF: 1.00 AC: 3854

ESP6500AA AF: 0.905 AC: 3965

ESP6500EA AF: 0.999 AC: 8562

ExAC AF: 0.990 AC: 119611

Asia WGS AF: 0.996 AC: 3463 AN: 3478

EpiCase AF: 1.00

EpiControl AF: 1.00

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

2-aminoadipic 2-oxoadipic aciduria Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Charcot-Marie-Tooth disease axonal type 2Q Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	1.7
Dann	Benign	0.56
DEOGEN2	Benign	0.000030	T;.
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.0087	N
LIST_S2	Benign	0.23	T;T
MetaRNN	Benign	9.9e-7	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.2	N;.
MutationTaster	Benign	1.0	P
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	0.20	N;N
REVEL	Benign	0.062
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;.
Vest4		0.014
MutPred		0.57		Loss of helix (P = 0.0033);Loss of helix (P = 0.0033);
MPC		0.13
ClinPred		0.0021	T
GERP RS		-0.088
Varity_R		0.058
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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

Other links and lift over

dbSNP: rs1279138; hg19: chr10-12111090; COSMIC: COSV53804524;