10-12069055-G-A

Variant names:

• chr10-12069055-G-A
• rs371803487
• NM_018706.7:c.22G>A

Variant summary

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

The NM_018706.7(DHTKD1):​c.22G>A​(p.Ala8Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,122 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: 𝑓 0.000020 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: DHTKD1 NM_018706.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.25

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=0.07585719).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DHTKD1	NM_018706.7	c.22G>A	p.Ala8Thr	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.22G>A	p.Ala8Thr	missense_variant	Exon 1 of 17	1	NM_018706.7	ENSP00000263035.4
DHTKD1	ENST00000437298.1	c.22G>A	p.Ala8Thr	missense_variant	Exon 1 of 5	3		ENSP00000388163.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152224 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000723

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000122 AC: 3 AN: 246180 Hom.: 0 AF XY: 0.0000149 AC XY: 2 AN XY: 134294

Gnomad AFR exome AF: 0.000198

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1460898 Hom.: 0 Cov.: 30 AF XY: 0.00000688 AC XY: 5 AN XY: 726800

Gnomad4 AFR exome AF: 0.000180

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152224 Hom.: 0 Cov.: 34 AF XY: 0.0000269 AC XY: 2 AN XY: 74370

Gnomad4 AFR AF: 0.0000723

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: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ESP6500AA AF: 0.000683 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00000825 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

2-aminoadipic 2-oxoadipic aciduria Uncertain:1

Jun 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 8 of the DHTKD1 protein (p.Ala8Thr). This variant is present in population databases (rs371803487, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with DHTKD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1426935). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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	0.15
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	16
DANN	Benign	0.95
DEOGEN2	Benign	0.0012	T;.
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.59	T;T
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.076	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.29	N;.
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.15	N;N
REVEL	Benign	0.077
Sift	Benign	0.18	T;T
Sift4G	Benign	0.39	T;T
Polyphen		0.0030	B;.
Vest4		0.32
MVP		0.055
MPC		0.11
ClinPred		0.086	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.6
Varity_R		0.085
gMVP		0.59

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: rs371803487; hg19: chr10-12111054;