rs3195676

Variant names:

Variant summary

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

The NM_001167595.2(AMACR):c.25G>A(p.Val9Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.482 in 1,610,698 control chromosomes in the GnomAD database, including 198,943 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 Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V9V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.41 ( 14732 hom., cov: 32)

Exomes 𝑓: 0.49 ( 184211 hom. )

Consequence

AMACR
NM_001167595.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.850

Publications

56 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=7.387839E-5).

BP6

Variant 5-34007995-C-T is Benign according to our data. Variant chr5-34007995-C-T is described in ClinVar as Benign. ClinVar VariationId is 128356.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.526 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001167595.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
AMACR	NM_014324.6	MANE Select	c.25G>A	p.Val9Met	missense	Exon 1 of 5	NP_055139.4
AMACR	NM_001167595.2		c.25G>A	p.Val9Met	missense	Exon 1 of 6	NP_001161067.1
AMACR	NM_203382.3		c.25G>A	p.Val9Met	missense	Exon 1 of 4	NP_976316.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
AMACR	ENST00000335606.11	TSL:1 MANE Select	c.25G>A	p.Val9Met	missense	Exon 1 of 5	ENSP00000334424.6
AMACR	ENST00000382085.7	TSL:1	c.25G>A	p.Val9Met	missense	Exon 1 of 6	ENSP00000371517.3
ENSG00000289791	ENST00000426255.6	TSL:2	c.25G>A	p.Val9Met	missense	Exon 1 of 5	ENSP00000476965.1

Frequencies

GnomAD3 genomes

AF:

0.412

AC:

62593

AN:

151940

Hom.:

14732

Cov.:

show subpopulations

Gnomad AFR

AF:

0.201

Gnomad AMI

AF:

0.554

Gnomad AMR

AF:

0.447

Gnomad ASJ

AF:

0.540

Gnomad EAS

AF:

0.344

Gnomad SAS

AF:

0.129

Gnomad FIN

AF:

0.536

Gnomad MID

AF:

0.331

Gnomad NFE

AF:

0.531

Gnomad OTH

AF:

0.416

GnomAD2 exomes

AF:

0.424

AC:

100169

AN:

236178

AF XY:

0.416

show subpopulations

Gnomad AFR exome

AF:

0.194

Gnomad AMR exome

AF:

0.425

Gnomad ASJ exome

AF:

0.540

Gnomad EAS exome

AF:

0.333

Gnomad FIN exome

AF:

0.526

Gnomad NFE exome

AF:

0.529

Gnomad OTH exome

AF:

0.454

GnomAD4 exome

AF:

0.490

AC:

714023

AN:

1458640

Hom.:

184211

Cov.:

AF XY:

0.480

AC XY:

348012

AN XY:

725690

show subpopulations

African (AFR)

AF:

0.185

AC:

6184

AN:

33460

American (AMR)

AF:

0.423

AC:

18907

AN:

44664

Ashkenazi Jewish (ASJ)

AF:

0.537

AC:

14006

AN:

26102

East Asian (EAS)

AF:

0.352

AC:

13972

AN:

39680

South Asian (SAS)

AF:

0.131

AC:

11289

AN:

86242

European-Finnish (FIN)

AF:

0.541

AC:

27532

AN:

50896

Middle Eastern (MID)

AF:

0.303

AC:

1745

AN:

5762

European-Non Finnish (NFE)

AF:

0.534

AC:

593002

AN:

1111518

Other (OTH)

AF:

0.454

AC:

27386

AN:

60316

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

22166

44332

66497

88663

110829

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16542

33084

49626

66168

82710

<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:

0.412

AC:

62597

AN:

152058

Hom.:

14732

Cov.:

AF XY:

0.408

AC XY:

30309

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.200

AC:

8313

AN:

41528

American (AMR)

AF:

0.447

AC:

6839

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.540

AC:

1872

AN:

3468

East Asian (EAS)

AF:

0.344

AC:

1774

AN:

5154

South Asian (SAS)

AF:

0.131

AC:

629

AN:

4812

European-Finnish (FIN)

AF:

0.536

AC:

5665

AN:

10578

Middle Eastern (MID)

AF:

0.322

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.531

AC:

36043

AN:

67916

Other (OTH)

AF:

0.410

AC:

865

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

1796

3593

5389

7186

8982

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

552

1104

1656

2208

2760

<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:

0.480

Hom.:

59778

Bravo

AF:

0.401

TwinsUK

AF:

0.540

AC:

2004

ALSPAC

AF:

0.535

AC:

2063

ESP6500AA

AF:

0.210

AC:

920

ESP6500EA

AF:

0.524

AC:

4492

ExAC

AF:

0.417

AC:

50167

Asia WGS

AF:

0.221

AC:

772

AN:

3478

EpiCase

AF:

0.538

EpiControl

AF:

0.537

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Alpha-methylacyl-CoA racemase deficiency (3)

not specified (3)

not provided (2)

Congenital bile acid synthesis defect 4 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.45

CADD

Benign

4.1

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.25

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.065

LIST_S2

Benign

0.80

MetaRNN

Benign

0.000074

MetaSVM

Benign

-0.90

MutationAssessor

Pathogenic

3.0

PhyloP100

-0.85

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-0.46

REVEL

Benign

0.23

Sift

Benign

0.038

Sift4G

Uncertain

0.0070

Polyphen

0.15

Vest4

0.11

MPC

0.94

ClinPred

0.043

GERP RS

-9.4

PromoterAI

0.085

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.16

gMVP

0.29

Mutation Taster

=100/0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over