rs145082938

Variant names:

Variant summary

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

The NM_004035.7(ACOX1):c.80C>T(p.Pro27Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00207 in 1,611,258 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P27S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0063 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0016 ( 24 hom. )

Consequence

ACOX1
NM_004035.7 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 4.24

Publications

5 publications found

Variant links:

Genes affected

ACOX1 (HGNC:119): (acyl-CoA oxidase 1) The protein encoded by this gene is the first enzyme of the fatty acid beta-oxidation pathway, which catalyzes the desaturation of acyl-CoAs to 2-trans-enoyl-CoAs. It donates electrons directly to molecular oxygen, thereby producing hydrogen peroxide. Defects in this gene result in pseudoneonatal adrenoleukodystrophy, a disease that is characterized by accumulation of very long chain fatty acids. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

ACOX1 links:

TEN1 (HGNC:37242): (TEN1 subunit of CST complex) C17ORF106, or TEN1, appears to function in a telomere-associated complex with STN1 (OBFC1; MIM 613128) and CTC1 (C17ORF68; MIM 613129) (Miyake et al., 2009 [PubMed 19854130]).[supplied by OMIM, Nov 2009]

TEN1 links:

TEN1-CDK3 (HGNC:44420): (TEN1-CDK3 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring TEN1 telomerase capping complex subunit homolog (S. cerevisiae) and cyclin-dependent kinase 3 (CDK3) genes. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is therefore unlikely to produce a protein product. [provided by RefSeq, Oct 2011]

TEN1-CDK3 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=0.00561586).

BP6

Variant 17-75978994-G-A is Benign according to our data. Variant chr17-75978994-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 235759.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00634 (966/152288) while in subpopulation AFR AF = 0.0186 (773/41560). AF 95% confidence interval is 0.0175. There are 5 homozygotes in GnomAd4. There are 450 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACOX1	NM_004035.7 link	c.80C>T	p.Pro27Leu	missense_variant	Exon 1 of 14	ENST00000293217.10	NP_004026.2
TEN1	NM_001113324.3 link	c.-524G>A		upstream_gene_variant		ENST00000397640.6	NP_001106795.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACOX1	ENST00000293217.10 link	c.80C>T	p.Pro27Leu	missense_variant	Exon 1 of 14	1	NM_004035.7	ENSP00000293217.4
TEN1	ENST00000397640.6 link	c.-524G>A		upstream_gene_variant		1	NM_001113324.3	ENSP00000380762.1

Frequencies

GnomAD3 genomes

AF:

0.00627

AC:

954

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0184

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00412

Gnomad ASJ

AF:

0.0127

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.000867

Gnomad OTH

AF:

0.00574

GnomAD2 exomes

AF:

0.00328

AC:

818

AN:

249350

AF XY:

0.00287

show subpopulations

Gnomad AFR exome

AF:

0.0184

Gnomad AMR exome

AF:

0.00428

Gnomad ASJ exome

AF:

0.0127

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0000985

Gnomad NFE exome

AF:

0.00125

Gnomad OTH exome

AF:

0.00883

GnomAD4 exome

AF:

0.00162

AC:

2365

AN:

1458970

Hom.:

Cov.:

AF XY:

0.00162

AC XY:

1177

AN XY:

726000

show subpopulations

African (AFR)

AF:

0.0183

AC:

611

AN:

33474

American (AMR)

AF:

0.00423

AC:

189

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0114

AC:

298

AN:

26130

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00161

AC:

139

AN:

86256

European-Finnish (FIN)

AF:

0.0000791

AC:

AN:

50588

Middle Eastern (MID)

AF:

0.0285

AC:

164

AN:

5764

European-Non Finnish (NFE)

AF:

0.000646

AC:

718

AN:

1111972

Other (OTH)

AF:

0.00399

AC:

241

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

165

330

494

659

824

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

126

168

210

<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:

0.00634

AC:

966

AN:

152288

Hom.:

Cov.:

AF XY:

0.00604

AC XY:

450

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.0186

AC:

773

AN:

41560

American (AMR)

AF:

0.00412

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0127

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5158

South Asian (SAS)

AF:

0.000622

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000867

AC:

AN:

68020

Other (OTH)

AF:

0.00568

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

135

180

225

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00288

Hom.:

Bravo

AF:

0.00751

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.0186

AC:

ESP6500EA

AF:

0.00128

AC:

ExAC

AF:

0.00328

AC:

398

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00229

EpiControl

AF:

0.00237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Acyl-CoA oxidase deficiency

Benign:4

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 11, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Aug 16, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Sep 28, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.42

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.47

.;T;.

Eigen

Benign

0.025

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.90

D;D;D

MetaRNN

Benign

0.0056

T;T;T

MetaSVM

Benign

-0.87

MutationAssessor

Benign

1.9

M;M;.

PhyloP100

4.2

PrimateAI

Benign

0.48

PROVEAN

Uncertain

-3.5

D;D;.

REVEL

Benign

0.11

Sift

Benign

0.090

T;T;.

Sift4G

Benign

0.20

T;T;.

Polyphen

0.0

B;B;.

Vest4

0.17

MVP

0.70

MPC

0.66

ClinPred

0.053

GERP RS

3.8

PromoterAI

-0.028

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.19

gMVP

0.66

Mutation Taster

=98/2

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over