rs117225135

Variant names:

• chr10-12112930-G-A
• rs117225135
• NM_018706.7:c.2185G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 1P and 6B. PP5 BP4 BS1_Supporting BS2

The NM_018706.7(DHTKD1):​c.2185G>A​(p.Gly729Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00266 in 1,610,968 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0027 (11 hom.)
• Consequence: DHTKD1 NM_018706.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:18 U:5
• Conservation: PhyloP100: 3.91
• Publications: 29 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: Labcorp Genetics (formerly Invitae), G2P, ClinGen
• Charcot-Marie-Tooth disease axonal type 2Q

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

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• PP5: Variant 10-12112930-G-A is Pathogenic according to our data. Variant chr10-12112930-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 39564.
• BP4: Computational evidence support a benign effect (MetaRNN=0.11351588). . Strength limited to SUPPORTING due to the PP5.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00186 (283/152220) while in subpopulation NFE AF = 0.00344 (234/68024). AF 95% confidence interval is 0.00308. There are 1 homozygotes in GnomAd4. There are 116 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 11 AR,AD gene

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.2185G>A	p.Gly729Arg	missense	Exon 13 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.2185G>A	p.Gly729Arg	missense	Exon 13 of 17	ENSP00000263035.4
	DHTKD1	ENST00000889958.1		c.2266G>A	p.Gly756Arg	missense	Exon 14 of 18	ENSP00000560017.1
	DHTKD1	ENST00000940762.1		c.2182G>A	p.Gly728Arg	missense	Exon 13 of 17	ENSP00000610821.1

Frequencies

GnomAD3 genomes AF: 0.00186 AC: 283 AN: 152102 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000852

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00344

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00166 AC: 412 AN: 248268 AF XY: 0.00176

Gnomad AFR exome AF: 0.000559

Gnomad AMR exome AF: 0.000474

Gnomad ASJ exome AF: 0.00210

Gnomad EAS exome AF: 0.000111

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.00272

Gnomad OTH exome AF: 0.00216

GnomAD4 exome AF: 0.00275 AC: 4009 AN: 1458748 Hom.: 11 Cov.: 31 AF XY: 0.00273 AC XY: 1983 AN XY: 725616

African (AFR) AF: 0.000570 AC: 19 AN: 33338

American (AMR) AF: 0.000475 AC: 21 AN: 44194

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 60 AN: 26042

East Asian (EAS) AF: 0.0000507 AC: 2 AN: 39424

South Asian (SAS) AF: 0.00167 AC: 143 AN: 85670

European-Finnish (FIN) AF: 0.0000937 AC: 5 AN: 53376

Middle Eastern (MID) AF: 0.00330 AC: 19 AN: 5762

European-Non Finnish (NFE) AF: 0.00323 AC: 3583 AN: 1110700

Other (OTH) AF: 0.00261 AC: 157 AN: 60242

GnomAD4 genome AF: 0.00186 AC: 283 AN: 152220 Hom.: 1 Cov.: 33 AF XY: 0.00156 AC XY: 116 AN XY: 74414

African (AFR) AF: 0.000385 AC: 16 AN: 41530

American (AMR) AF: 0.000851 AC: 13 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00344 AC: 234 AN: 68024

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00274 Hom.: 1

Bravo AF: 0.00192

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00233 AC: 20

ExAC AF: 0.00155 AC: 188

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00384

EpiControl AF: 0.00275

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
10	-	-	2-aminoadipic 2-oxoadipic aciduria (10)
4	2	-	not provided (6)
1	1	-	not specified (2)
-	1	-	Charcot-Marie-Tooth disease type 2A2 (1)
1	-	-	DHTKD1-related disorder (1)
-	1	-	Inborn disorder of lysine and hydroxylysine metabolism (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Tip-toe gait (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.30	T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Pathogenic	0.38	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		3.9
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-6.0	D
REVEL	Benign	0.23
Sift	Uncertain	0.0060	D
Sift4G	Benign	0.074	T
Polyphen		0.98	D
Vest4		0.82
MutPred		0.62		Gain of loop (P = 0.069)
MVP		0.39
MPC		0.20
ClinPred		0.041	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.76
gMVP		0.78
Mutation Taster		=17/83	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs117225135; hg19: chr10-12154929; COSMIC: COSV53805911; COSMIC: COSV53805911;