10-12069068-G-T

Variant names:

• chr10-12069068-G-T
• rs1042683604
• NM_018706.7:c.35G>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_018706.7(DHTKD1):​c.35G>T​(p.Gly12Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,460,672 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: DHTKD1 NM_018706.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0770

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 Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07643601).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DHTKD1	NM_018706.7	c.35G>T	p.Gly12Val	missense_variant	Exon 1 of 17	ENST00000263035.9	NP_061176.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DHTKD1	ENST00000263035.9	c.35G>T	p.Gly12Val	missense_variant	Exon 1 of 17	1	NM_018706.7	ENSP00000263035.4
DHTKD1	ENST00000437298.1	c.35G>T	p.Gly12Val	missense_variant	Exon 1 of 5	3		ENSP00000388163.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1460672 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726678

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: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

2-aminoadipic 2-oxoadipic aciduria Uncertain:1

Dec 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 12 of the DHTKD1 protein (p.Gly12Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with DHTKD1-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Not Available". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	7.7
DANN	Benign	0.69
DEOGEN2	Benign	0.0012	T;.
Eigen	Benign	-0.95
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.54	T;T
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.076	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.90	L;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.18	N;N
REVEL	Benign	0.060
Sift	Benign	0.18	T;T
Sift4G	Benign	0.36	T;T
Polyphen		0.0080	B;.
Vest4		0.14
MutPred		0.48		Loss of loop (P = 0.0112);Loss of loop (P = 0.0112);
MVP		0.088
MPC		0.14
ClinPred		0.064	T
GERP RS		0.64
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.042
gMVP		0.44

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: rs1042683604; hg19: chr10-12111067;