rs75134564

chr5-41862656-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000436.4(OXCT1):c.173C>T(p.Thr58Met) variant causes a missense change. The variant allele was found at a frequency of 0.00042 in 1,606,366 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00040 (5 hom.)
• Consequence: OXCT1 NM_000436.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 3.93

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.028270483).
• BP6: Variant 5-41862656-G-A is Benign according to our data. Variant chr5-41862656-G-A is described in ClinVar as [Benign]. Clinvar id is 242800.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-41862656-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000592 (90/151946) while in subpopulation EAS AF= 0.012 (62/5172). AF 95% confidence interval is 0.0096. There are 0 homozygotes in gnomad4. There are 52 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OXCT1	NM_000436.4	c.173C>T	p.Thr58Met	missense_variant	2/17	ENST00000196371.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OXCT1	ENST00000196371.10	c.173C>T	p.Thr58Met	missense_variant	2/17	1	NM_000436.4	P1

Frequencies

GnomAD3 genomes AF: 0.000586 AC: 89 AN: 151828 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000363

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0118

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000950

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00132 AC: 332 AN: 251382 Hom.: 4 AF XY: 0.00127 AC XY: 172 AN XY: 135876

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0165

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000880

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000402 AC: 585 AN: 1454420 Hom.: 5 Cov.: 29 AF XY: 0.000383 AC XY: 277 AN XY: 724034

Gnomad4 AFR exome AF: 0.000420

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00947

Gnomad4 SAS exome AF: 0.000105

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000107

Gnomad4 OTH exome AF: 0.000964

GnomAD4 genome AF: 0.000592 AC: 90 AN: 151946 Hom.: 0 Cov.: 32 AF XY: 0.000701 AC XY: 52 AN XY: 74232

Gnomad4 AFR AF: 0.000362

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0120

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.0000950

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.000713 Hom.: 2

Bravo AF: 0.000986

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00133 AC: 162

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Succinyl-CoA acetoacetate transferase deficiency Benign:4

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 08, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Likely benign, no assertion criteria provided	curation	SingHealth Duke-NUS Institute of Precision Medicine	Jun 07, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 23, 2022	- -

not provided Benign:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 14, 2017	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 16, 2017	- -

OXCT1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 11, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.090
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D
Eigen	Benign	-0.013
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Pathogenic	0.98	D
MetaRNN	Benign	0.028	T
MetaSVM	Uncertain	0.55	D
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	0.000018	A
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.35
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.012	D
Polyphen		1.0	D
Vest4		0.50
MVP		0.68
MPC		1.3
ClinPred		0.043	T
GERP RS		1.4
Varity_R		0.069
gMVP		0.85

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: rs75134564; hg19: chr5-41862758; COSMIC: COSV52178410;