10-12089191-G-T

Position:

• chr10-12089191-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000263035.9(DHTKD1):​c.923G>T​(p.Arg308Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R308H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DHTKD1 ENST00000263035.9 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.99

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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05337873).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DHTKD1	NM_018706.7	c.923G>T	p.Arg308Leu	missense_variant	5/17	ENST00000263035.9	NP_061176.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DHTKD1	ENST00000263035.9	c.923G>T	p.Arg308Leu	missense_variant	5/17	1	NM_018706.7	ENSP00000263035	P1
DHTKD1	ENST00000437298.1	c.728G>T	p.Arg243Leu	missense_variant	4/5	3		ENSP00000388163
DHTKD1	ENST00000415935.1	c.17G>T	p.Arg6Leu	missense_variant	1/3	2		ENSP00000400625
DHTKD1	ENST00000465617.1	n.299+1462G>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Uncertain	0.050	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	11
DANN	Benign	0.12
DEOGEN2	Benign	0.045	T;.;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.22	N
LIST_S2	Uncertain	0.87	D;D;T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.053	T;T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	-0.29	N;.;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	1.2	N;N;N
REVEL	Benign	0.17
Sift	Benign	0.54	T;T;T
Sift4G	Benign	0.55	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.20
MutPred		0.49		Loss of MoRF binding (P = 0.0366);.;.;
MVP		0.27
MPC		0.14
ClinPred		0.059	T
GERP RS		3.2
Varity_R		0.14
gMVP		0.54

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: rs17849603; hg19: chr10-12131190;