5-41862656-G-C

Variant names:

• chr5-41862656-G-C
• rs75134564
• NM_000436.4:c.173C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000436.4(OXCT1):​c.173C>G​(p.Thr58Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,454,428 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T58M) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: OXCT1 NM_000436.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.93
• Publications: 0 publications found

Genes affected

OXCT1 (HGNC:8527): (3-oxoacid CoA-transferase 1) This gene encodes a member of the 3-oxoacid CoA-transferase gene family. The encoded protein is a homodimeric mitochondrial matrix enzyme that plays a central role in extrahepatic ketone body catabolism by catalyzing the reversible transfer of coenzyme A from succinyl-CoA to acetoacetate. Mutations in this gene are associated with succinyl CoA:3-oxoacid CoA transferase deficiency. [provided by RefSeq, Jul 2008]

OXCT1 Gene-Disease associations (from GenCC):

• succinyl-CoA:3-ketoacid CoA transferase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, Illumina, Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000436.4. 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
	OXCT1	NM_000436.4	MANE Select	c.173C>G	p.Thr58Arg	missense	Exon 2 of 17	NP_000427.1	P55809-1
	OXCT1	NM_001364299.2		c.173C>G	p.Thr58Arg	missense	Exon 2 of 18	NP_001351228.1
	OXCT1	NM_001364300.2		c.194C>G	p.Thr65Arg	missense	Exon 2 of 17	NP_001351229.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OXCT1	ENST00000196371.10	TSL:1 MANE Select	c.173C>G	p.Thr58Arg	missense	Exon 2 of 17	ENSP00000196371.5	P55809-1
	OXCT1	ENST00000972071.1		c.173C>G	p.Thr58Arg	missense	Exon 2 of 18	ENSP00000642130.1
	OXCT1	ENST00000919063.1		c.173C>G	p.Thr58Arg	missense	Exon 2 of 18	ENSP00000589122.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1454428 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 724034

African (AFR) AF: 0.00 AC: 0 AN: 33330

American (AMR) AF: 0.00 AC: 0 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26078

East Asian (EAS) AF: 0.00 AC: 0 AN: 39616

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86110

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105328

Other (OTH) AF: 0.00 AC: 0 AN: 60136

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Uncertain	0.077	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	14
DANN	Benign	0.97
DEOGEN2	Uncertain	0.44	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.63
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.043	D
MetaRNN	Uncertain	0.54	D
MetaSVM	Benign	-0.47	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		3.9
PrimateAI	Benign	0.37	T
PROVEAN	Benign	0.85	N
REVEL	Uncertain	0.32
Sift	Benign	0.034	D
Sift4G	Uncertain	0.040	D
Polyphen		0.16	B
Vest4		0.50
MutPred		0.73		Gain of methylation at T58 (P = 0.0346)
MVP		0.50
MPC		1.0
ClinPred		0.53	D
GERP RS		1.4
Varity_R		0.13
gMVP		0.95
Mutation Taster		=50/50

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: rs75134564; hg19: chr5-41862758;