dbSNP rs140021599: AMACR:p.Leu385Val (chr5-33988340-A-C) – 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_001167595.2(AMACR):c.1153T>G(p.Leu385Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00125 in 1,541,968 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0066 ( 10 hom., cov: 32)

Exomes 𝑓: 0.00067 ( 18 hom. )

Consequence

AMACR
NM_001167595.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.59

Publications

0 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:

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=0.0035224557).

BP6

Variant 5-33988340-A-C is Benign according to our data. Variant chr5-33988340-A-C is described in ClinVar as Benign. ClinVar VariationId is 353242.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 = 0.00655 (998/152286) while in subpopulation AFR AF = 0.0231 (960/41552). AF 95% confidence interval is 0.0219. There are 10 homozygotes in GnomAd4. There are 493 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 10 AR gene

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	UniProt
AMACR	NM_014324.6	MANE Select	c.*753T>G		3_prime_UTR	Exon 5 of 5	NP_055139.4
AMACR	NM_001167595.2		c.1153T>G	p.Leu385Val	missense	Exon 6 of 6	NP_001161067.1	Q9UHK6-5
AMACR	NM_203382.3		c.*1144T>G		3_prime_UTR	Exon 4 of 4	NP_976316.1	Q9UHK6-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AMACR	ENST00000382085.7	TSL:1	c.1153T>G	p.Leu385Val	missense	Exon 6 of 6	ENSP00000371517.3	Q9UHK6-5
AMACR	ENST00000335606.11	TSL:1 MANE Select	c.*753T>G		3_prime_UTR	Exon 5 of 5	ENSP00000334424.6	Q9UHK6-1
AMACR	ENST00000382072.6	TSL:1	c.*1144T>G		3_prime_UTR	Exon 4 of 4	ENSP00000371504.2	Q9UHK6-4

Frequencies

GnomAD3 genomes

AF:

0.00652

AC:

992

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0230

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00716

GnomAD2 exomes

AF:

0.00138

AC:

210

AN:

152046

AF XY:

0.00111

show subpopulations

Gnomad AFR exome

AF:

0.0214

Gnomad AMR exome

AF:

0.000879

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000880

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000469

Gnomad OTH exome

AF:

0.000450

GnomAD4 exome

AF:

0.000669

AC:

930

AN:

1389682

Hom.:

Cov.:

AF XY:

0.000567

AC XY:

389

AN XY:

686136

show subpopulations

African (AFR)

AF:

0.0229

AC:

729

AN:

31868

American (AMR)

AF:

0.00116

AC:

AN:

36146

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25216

East Asian (EAS)

AF:

0.00

AC:

AN:

36382

South Asian (SAS)

AF:

0.000138

AC:

AN:

79478

European-Finnish (FIN)

AF:

0.00

AC:

AN:

35424

Middle Eastern (MID)

AF:

0.00245

AC:

AN:

5704

European-Non Finnish (NFE)

AF:

0.0000305

AC:

AN:

1081286

Other (OTH)

AF:

0.00174

AC:

101

AN:

58178

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

131

174

218

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

130

<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:

0.00655

AC:

998

AN:

152286

Hom.:

Cov.:

AF XY:

0.00662

AC XY:

493

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.0231

AC:

960

AN:

41552

American (AMR)

AF:

0.00124

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68020

Other (OTH)

AF:

0.00709

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

145

193

241

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:

0.00713

ESP6500AA

AF:

0.0206

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00112

AC:

123

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Alpha-methylacyl-CoA racemase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.59

CADD

Benign

8.5

(source)

DANN

Benign

0.82

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.92

FATHMM_MKL

Benign

0.060

LIST_S2

Benign

0.29

MetaRNN

Benign

0.0035

MetaSVM

Benign

-1.0

PhyloP100

1.6

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.030

REVEL

Benign

0.057

Sift

Pathogenic

0.0

Sift4G

Benign

0.27

Vest4

0.21

MVP

0.32

MPC

0.058

ClinPred

0.039

GERP RS

1.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.22

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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