rs9282594

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_014324.6(AMACR):c.712C>T(p.Pro238Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00445 in 1,612,120 control chromosomes in the GnomAD database, including 268 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P238L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.024 ( 144 hom., cov: 32)

Exomes 𝑓: 0.0024 ( 124 hom. )

Consequence

AMACR
NM_014324.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 5.45

Publications

9 publications found

Variant links:

Genes affected

AMACR (HGNC:451): (alpha-methylacyl-CoA racemase) This gene encodes a racemase. The encoded enzyme interconverts pristanoyl-CoA and C27-bile acylCoAs between their (R)- and (S)-stereoisomers. The conversion to the (S)-stereoisomers is necessary for degradation of these substrates by peroxisomal beta-oxidation. Encoded proteins from this locus localize to both mitochondria and peroxisomes. Mutations in this gene may be associated with adult-onset sensorimotor neuropathy, pigmentary retinopathy, and adrenomyeloneuropathy due to defects in bile acid synthesis. Alternatively spliced transcript variants have been described. Read-through transcription also exists between this gene and the upstream neighboring C1QTNF3 (C1q and tumor necrosis factor related protein 3) gene. [provided by RefSeq, Mar 2011]

AMACR links:

ENSG00000289791 (HGNC:):

ENSG00000289791 links:

C1QTNF3-AMACR (HGNC:49198): (C1QTNF3-AMACR readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring C1q and tumor necrosis factor related protein 3 (C1QTNF3) and alpha-methylacyl-CoA racemase (AMACR) genes on chromosome 5. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is thus not likely to produce a protein product. [provided by RefSeq, Mar 2011]

C1QTNF3-AMACR 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=0.0028857589).

BP6

Variant 5-33998668-G-A is Benign according to our data. Variant chr5-33998668-G-A is described in ClinVar as Benign. ClinVar VariationId is 353254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0811 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AMACR	NM_014324.6 link	c.712C>T	p.Pro238Ser	missense_variant	Exon 4 of 5	ENST00000335606.11	NP_055139.4	Q9UHK6-1
AMACR	NM_001167595.2 link	c.712C>T	p.Pro238Ser	missense_variant	Exon 4 of 6		NP_001161067.1	Q9UHK6-5
AMACR	NM_203382.3 link	c.551C>T	p.Thr184Ile	missense_variant	Exon 3 of 4		NP_976316.1	Q9UHK6-4
C1QTNF3-AMACR	NR_037951.1 link	n.1068C>T		non_coding_transcript_exon_variant	Exon 8 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
AMACR	ENST00000335606.11 link	c.712C>T	p.Pro238Ser	missense_variant	Exon 4 of 5	1	NM_014324.6	ENSP00000334424.6	Q9UHK6-1
ENSG00000289791	ENST00000426255.6 link	c.712C>T	p.Pro238Ser	missense_variant	Exon 4 of 5	2		ENSP00000476965.1	V9GYP4
C1QTNF3-AMACR	ENST00000382079.3 link	n.*138C>T		non_coding_transcript_exon_variant	Exon 8 of 9	2		ENSP00000371511.3	E9PGA6
C1QTNF3-AMACR	ENST00000382079.3 link	n.*138C>T		3_prime_UTR_variant	Exon 8 of 9	2		ENSP00000371511.3	E9PGA6

Frequencies

GnomAD3 genomes

AF:

0.0238

AC:

3615

AN:

151946

Hom.:

141

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0831

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00860

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.0159

GnomAD2 exomes

AF:

0.00629

AC:

1578

AN:

250676

AF XY:

0.00474

show subpopulations

Gnomad AFR exome

AF:

0.0861

Gnomad AMR exome

AF:

0.00349

Gnomad ASJ exome

AF:

0.0000996

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000326

Gnomad OTH exome

AF:

0.00278

GnomAD4 exome

AF:

0.00242

AC:

3539

AN:

1460056

Hom.:

124

Cov.:

AF XY:

0.00207

AC XY:

1501

AN XY:

726038

show subpopulations

African (AFR)

AF:

0.0849

AC:

2838

AN:

33444

American (AMR)

AF:

0.00419

AC:

187

AN:

44614

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26078

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39660

South Asian (SAS)

AF:

0.000244

AC:

AN:

86090

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00712

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.000123

AC:

137

AN:

1110678

Other (OTH)

AF:

0.00519

AC:

313

AN:

60320

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

158

315

473

630

788

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

188

282

376

470

<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:

0.0239

AC:

3637

AN:

152064

Hom.:

144

Cov.:

AF XY:

0.0229

AC XY:

1700

AN XY:

74356

show subpopulations

African (AFR)

AF:

0.0834

AC:

3456

AN:

41434

American (AMR)

AF:

0.00852

AC:

130

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.000622

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000191

AC:

AN:

68004

Other (OTH)

AF:

0.0157

AC:

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

164

328

491

655

819

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

160

200

<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:

0.00863

Hom.:

183

Bravo

AF:

0.0279

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.0790

AC:

348

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00786

AC:

954

Asia WGS

AF:

0.00491

AC:

AN:

3478

EpiCase

AF:

0.000328

EpiControl

AF:

0.000296

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Dec 16, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Alpha-methylacyl-CoA racemase deficiency

Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

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. -

not specified

Benign:1

Dec 10, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.31

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

T;.;.;T;T

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.98

D;D;D;D;D

MetaRNN

Benign

0.0029

T;T;T;T;T

MetaSVM

Benign

-0.58

MutationAssessor

Uncertain

2.2

M;M;.;.;.

PhyloP100

5.4

PrimateAI

Uncertain

0.49

PROVEAN

Pathogenic

-6.0

D;D;D;.;.

REVEL

Uncertain

0.31

Sift

Benign

0.056

T;D;T;.;.

Sift4G

Uncertain

0.046

D;D;D;D;D

Polyphen

0.83

P;.;P;.;.

Vest4

0.30

MVP

0.74

MPC

0.12

ClinPred

0.051

GERP RS

5.3

Varity_R

0.47

gMVP

0.78

Mutation Taster

=92/8

polymorphism (auto)

(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