Genetic Variant NM_000436.4:c.173C>T (chr5-41862656-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 3.93

Publications

13 publications found

Variant links:

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

OXCT1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 242800.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 5 AR gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
OXCT1	NM_000436.4	MANE Select	c.173C>T	p.Thr58Met	missense	Exon 2 of 17	NP_000427.1	P55809-1
OXCT1	NM_001364299.2		c.173C>T	p.Thr58Met	missense	Exon 2 of 18	NP_001351228.1
OXCT1	NM_001364300.2		c.194C>T	p.Thr65Met	missense	Exon 2 of 17	NP_001351229.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
OXCT1	ENST00000196371.10	TSL:1 MANE Select	c.173C>T	p.Thr58Met	missense	Exon 2 of 17	ENSP00000196371.5	P55809-1
OXCT1	ENST00000972071.1		c.173C>T	p.Thr58Met	missense	Exon 2 of 18	ENSP00000642130.1
OXCT1	ENST00000919063.1		c.173C>T	p.Thr58Met	missense	Exon 2 of 18	ENSP00000589122.1

Frequencies

GnomAD3 genomes

AF:

0.000586

AC:

AN:

151828

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00132

AC:

332

AN:

251382

AF XY:

0.00127

show subpopulations

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 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.:

Cov.:

AF XY:

0.000383

AC XY:

277

AN XY:

724034

show subpopulations

African (AFR)

AF:

0.000420

AC:

AN:

33330

American (AMR)

AF:

0.000201

AC:

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26078

East Asian (EAS)

AF:

0.00947

AC:

375

AN:

39610

South Asian (SAS)

AF:

0.000105

AC:

AN:

86110

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53390

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

0.000107

AC:

118

AN:

1105326

Other (OTH)

AF:

0.000964

AC:

AN:

60136

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

113

141

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000592

AC:

AN:

151946

Hom.:

Cov.:

AF XY:

0.000701

AC XY:

AN XY:

74232

show subpopulations

African (AFR)

AF:

0.000362

AC:

AN:

41398

American (AMR)

AF:

0.000196

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.0120

AC:

AN:

5172

South Asian (SAS)

AF:

0.000208

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.0000950

AC:

AN:

10524

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

67978

Other (OTH)

AF:

0.00190

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000543

Hom.:

Bravo

AF:

0.000986

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00133

AC:

162

Asia WGS

AF:

0.00433

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Succinyl-CoA acetoacetate transferase deficiency (4)

not provided (2)

OXCT1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.090

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.58

Eigen

Benign

-0.013

Eigen_PC

Benign

-0.19

FATHMM_MKL

Uncertain

0.86

LIST_S2

Pathogenic

0.98

MetaRNN

Benign

0.028

MetaSVM

Uncertain

0.55

MutationAssessor

Uncertain

2.6

PhyloP100

3.9

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.1

REVEL

Uncertain

0.35

Sift

Uncertain

0.011

Sift4G

Uncertain

0.012

Polyphen

1.0

Vest4

0.50

MVP

0.68

MPC

1.3

ClinPred

0.043

GERP RS

1.4

Varity_R

0.069

gMVP

0.85

Mutation Taster

=60/40

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over