rs750604881

Variant names:

• chr5-41805669-G-A
• rs750604881
• NM_000436.4:c.853C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-41805669-G-A
• chr5-41805669-G-T

Variant summary

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

The NM_000436.4(OXCT1):​c.853C>T​(p.Arg285Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000468 in 1,603,988 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R285Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000048 (0 hom.)
• Consequence: OXCT1 NM_000436.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.38
• Publications: 1 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.853C>T	p.Arg285Trp	missense	Exon 9 of 17	NP_000427.1	P55809-1
	OXCT1	NM_001364299.2		c.874C>T	p.Arg292Trp	missense	Exon 10 of 18	NP_001351228.1
	OXCT1	NM_001364300.2		c.874C>T	p.Arg292Trp	missense	Exon 9 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.853C>T	p.Arg285Trp	missense	Exon 9 of 17	ENSP00000196371.5	P55809-1
	OXCT1	ENST00000972071.1		c.853C>T	p.Arg285Trp	missense	Exon 9 of 18	ENSP00000642130.1
	OXCT1	ENST00000919063.1		c.853C>T	p.Arg285Trp	missense	Exon 9 of 18	ENSP00000589122.1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 151856 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000736

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000558 AC: 14 AN: 251082 AF XY: 0.0000516

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000968

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000482 AC: 70 AN: 1452132 Hom.: 0 Cov.: 29 AF XY: 0.0000526 AC XY: 38 AN XY: 723084

African (AFR) AF: 0.0000601 AC: 2 AN: 33264

American (AMR) AF: 0.00 AC: 0 AN: 44608

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26032

East Asian (EAS) AF: 0.00 AC: 0 AN: 39636

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86044

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.0000598 AC: 66 AN: 1103380

Other (OTH) AF: 0.0000167 AC: 1 AN: 60044

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 151856 Hom.: 0 Cov.: 32 AF XY: 0.0000540 AC XY: 4 AN XY: 74128

African (AFR) AF: 0.00 AC: 0 AN: 41366

American (AMR) AF: 0.00 AC: 0 AN: 15216

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10558

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000736 AC: 5 AN: 67942

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000826 Hom.: 0

Bravo AF: 0.0000264

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000577 AC: 7

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Succinyl-CoA acetoacetate transferase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.015	T
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.055	D
MetaRNN	Uncertain	0.50	T
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		3.4
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.44
Sift	Benign	0.042	D
Sift4G	Uncertain	0.056	T
Polyphen		0.021	B
Vest4		0.57
MVP		0.57
MPC		0.71
ClinPred		0.17	T
GERP RS		5.7
Varity_R		0.27
gMVP		0.76
Mutation Taster		=67/33	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs750604881; hg19: chr5-41805771;