NM_018706.7:c.58T>C

Variant names:

• chr10-12069091-T-C
• rs1279138
• NM_018706.7:c.58T>C

Variant summary

Our verdict is Benign. The variant received -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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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:6
• Conservation: PhyloP100: -0.834
• Publications: 23 publications found

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 Gene-Disease associations (from GenCC):

• 2-aminoadipic 2-oxoadipic aciduria

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen
• Charcot-Marie-Tooth disease axonal type 2Q

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ENSG00000294071 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 1168371.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018706.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DHTKD1	NM_018706.7	MANE Select	c.58T>C	p.Phe20Leu	missense	Exon 1 of 17	NP_061176.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DHTKD1	ENST00000263035.9	TSL:1 MANE Select	c.58T>C	p.Phe20Leu	missense	Exon 1 of 17	ENSP00000263035.4	Q96HY7
	DHTKD1	ENST00000889958.1		c.58T>C	p.Phe20Leu	missense	Exon 1 of 18	ENSP00000560017.1
	DHTKD1	ENST00000940762.1		c.58T>C	p.Phe20Leu	missense	Exon 1 of 17	ENSP00000610821.1

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

GnomAD2 exomes AF: 0.992 AC: 242883 AN: 244766 AF XY: 0.994

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 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

African (AFR) AF: 0.895 AC: 29880 AN: 33392

American (AMR) AF: 0.994 AC: 44427 AN: 44700

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 26084 AN: 26084

East Asian (EAS) AF: 1.00 AC: 39670 AN: 39670

South Asian (SAS) AF: 1.00 AC: 86170 AN: 86184

European-Finnish (FIN) AF: 0.999 AC: 52891 AN: 52958

Middle Eastern (MID) AF: 0.997 AC: 5462 AN: 5478

European-Non Finnish (NFE) AF: 1.00 AC: 1111392 AN: 1111578

Other (OTH) AF: 0.994 AC: 59865 AN: 60248

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

African (AFR) AF: 0.895 AC: 37198 AN: 41580

American (AMR) AF: 0.989 AC: 15142 AN: 15308

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3472 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5172 AN: 5172

South Asian (SAS) AF: 1.00 AC: 4829 AN: 4830

European-Finnish (FIN) AF: 0.999 AC: 10622 AN: 10630

Middle Eastern (MID) AF: 0.993 AC: 292 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 67992 AN: 68018

Other (OTH) AF: 0.980 AC: 2071 AN: 2114

Alfa AF: 0.986 Hom.: 41536

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	2-aminoadipic 2-oxoadipic aciduria (2)
-	-	2	not specified (2)
-	-	1	Charcot-Marie-Tooth disease axonal type 2Q (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	9.9e-7	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.2	N
PhyloP100		-0.83
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	0.20	N
REVEL	Benign	0.062
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.014
MutPred		0.57		Loss of helix (P = 0.0033)
MPC		0.13
ClinPred		0.0021	T
GERP RS		-0.088
PromoterAI		-0.032	Neutral
Varity_R		0.058
gMVP		0.34
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

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