rs181341030

Positions:

chr5-33989398-C-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_014324.6(AMACR):c.844G>C(p.Glu282Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000237 in 1,614,212 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E282D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00029 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00023 ( 5 hom. )

Consequence

AMACR
NM_014324.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:4

Conservation

PhyloP100: 7.61

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:):

C1QTNF3-AMACR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012740344).

BP6

Variant 5-33989398-C-G is Benign according to our data. Variant chr5-33989398-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 210135.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=3}.

BS2

High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
AMACR	NM_014324.6 linkuse as main transcript	c.844G>C	p.Glu282Gln	missense_variant	5/5	ENST00000335606.11
C1QTNF3-AMACR	NR_037951.1 linkuse as main transcript	n.1200G>C		non_coding_transcript_exon_variant	9/9
AMACR	NM_001167595.2 linkuse as main transcript	c.844G>C	p.Glu282Gln	missense_variant	5/6
AMACR	NM_203382.3 linkuse as main transcript	c.*86G>C		3_prime_UTR_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AMACR	ENST00000335606.11 linkuse as main transcript	c.844G>C	p.Glu282Gln	missense_variant	5/5	1	NM_014324.6	P1	Q9UHK6-1

Frequencies

GnomAD3 genomes

AF:

0.000289

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00653

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000688

AC:

173

AN:

251474

Hom.:

AF XY:

0.000714

AC XY:

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00777

Gnomad SAS exome

AF:

0.000719

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.000978

GnomAD4 exome

AF:

0.000231

AC:

338

AN:

1461874

Hom.:

Cov.:

AF XY:

0.000250

AC XY:

182

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00461

Gnomad4 SAS exome

AF:

0.000800

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00134

GnomAD4 genome

AF:

0.000289

AC:

AN:

152338

Hom.:

Cov.:

AF XY:

0.000403

AC XY:

AN XY:

74514

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00655

Gnomad4 SAS

AF:

0.00207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000139

Hom.:

Bravo

AF:

0.000393

ExAC

AF:

0.000651

AC:

Asia WGS

AF:

0.00433

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 23, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 13, 2014	- -

Alpha-methylacyl-CoA racemase deficiency

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -

Mitochondrial complex I deficiency

Uncertain:1

Uncertain significance, criteria provided, single submitter

reference population

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

Mar 18, 2016

- -

Congenital bile acid synthesis defect 4;C3280428:Alpha-methylacyl-CoA racemase deficiency

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

AMACR-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 08, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.081

BayesDel_noAF

Uncertain

0.12

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

T;.;.

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D;D

M_CAP

Benign

0.027

MetaRNN

Benign

0.013

T;T;T

MetaSVM

Benign

-0.35

MutationAssessor

Uncertain

2.6

M;M;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-2.5

D;N;N

REVEL

Uncertain

0.38

Sift

Benign

0.097

T;T;T

Sift4G

Benign

0.078

T;T;T

Polyphen

0.99

D;.;D

Vest4

0.55

MVP

0.77

MPC

0.27

ClinPred

0.10

GERP RS

5.7

Varity_R

0.56

gMVP

0.65

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over