rs10941112

Variant names:

• chr5-34004602-C-T
• rs10941112
• NM_014324.6:c.524G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014324.6(AMACR):​c.524G>A​(p.Gly175Asp) variant causes a missense change. The variant allele was found at a frequency of 0.475 in 1,613,804 control chromosomes in the GnomAD database, including 196,459 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (13929 hom., cov: 32)
  • Exomes 𝑓: 0.48 (182530 hom.)
• Consequence: AMACR NM_014324.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 4.50
• Publications: 69 publications found

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]

ENSG00000289791 (HGNC:):

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]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0040152073).
• BP6: Variant 5-34004602-C-T is Benign according to our data. Variant chr5-34004602-C-T is described in ClinVar as Benign. ClinVar VariationId is 128357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.524 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AMACR	NM_014324.6	c.524G>A	p.Gly175Asp	missense_variant	Exon 3 of 5	ENST00000335606.11	NP_055139.4
AMACR	NM_001167595.2	c.524G>A	p.Gly175Asp	missense_variant	Exon 3 of 6		NP_001161067.1
AMACR	NM_203382.3	c.391+1154G>A		intron_variant	Intron 2 of 3		NP_976316.1
C1QTNF3-AMACR	NR_037951.1	n.908+1154G>A		intron_variant	Intron 7 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AMACR	ENST00000335606.11	c.524G>A	p.Gly175Asp	missense_variant	Exon 3 of 5	1	NM_014324.6	ENSP00000334424.6
ENSG00000289791	ENST00000426255.6	c.524G>A	p.Gly175Asp	missense_variant	Exon 3 of 5	2		ENSP00000476965.1
C1QTNF3-AMACR	ENST00000382079.3	n.833+1154G>A		intron_variant	Intron 7 of 8	2		ENSP00000371511.3

Frequencies

GnomAD3 genomes AF: 0.381 AC: 57872 AN: 151898 Hom.: 13930 Cov.: 32

Gnomad AFR AF: 0.0967

Gnomad AMI AF: 0.556

Gnomad AMR AF: 0.435

Gnomad ASJ AF: 0.540

Gnomad EAS AF: 0.341

Gnomad SAS AF: 0.127

Gnomad FIN AF: 0.535

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.529

Gnomad OTH AF: 0.389

GnomAD2 exomes AF: 0.420 AC: 105515 AN: 251448 AF XY: 0.413

Gnomad AFR exome AF: 0.0891

Gnomad AMR exome AF: 0.412

Gnomad ASJ exome AF: 0.540

Gnomad EAS exome AF: 0.330

Gnomad FIN exome AF: 0.530

Gnomad NFE exome AF: 0.529

Gnomad OTH exome AF: 0.451

GnomAD4 exome AF: 0.485 AC: 708537 AN: 1461788 Hom.: 182530 Cov.: 59 AF XY: 0.475 AC XY: 345628 AN XY: 727190

African (AFR) AF: 0.0771 AC: 2581 AN: 33474

American (AMR) AF: 0.411 AC: 18372 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.537 AC: 14023 AN: 26134

East Asian (EAS) AF: 0.349 AC: 13851 AN: 39694

South Asian (SAS) AF: 0.129 AC: 11161 AN: 86258

European-Finnish (FIN) AF: 0.541 AC: 28923 AN: 53416

Middle Eastern (MID) AF: 0.296 AC: 1706 AN: 5766

European-Non Finnish (NFE) AF: 0.532 AC: 591007 AN: 1111930

Other (OTH) AF: 0.446 AC: 26913 AN: 60392

GnomAD4 genome AF: 0.381 AC: 57866 AN: 152016 Hom.: 13929 Cov.: 32 AF XY: 0.377 AC XY: 28039 AN XY: 74286

African (AFR) AF: 0.0964 AC: 4002 AN: 41496

American (AMR) AF: 0.435 AC: 6642 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.540 AC: 1875 AN: 3470

East Asian (EAS) AF: 0.341 AC: 1758 AN: 5156

South Asian (SAS) AF: 0.128 AC: 617 AN: 4814

European-Finnish (FIN) AF: 0.535 AC: 5637 AN: 10538

Middle Eastern (MID) AF: 0.330 AC: 97 AN: 294

European-Non Finnish (NFE) AF: 0.529 AC: 35922 AN: 67954

Other (OTH) AF: 0.385 AC: 811 AN: 2108

Alfa AF: 0.477 Hom.: 77191

Bravo AF: 0.365

TwinsUK AF: 0.539 AC: 1997

ALSPAC AF: 0.534 AC: 2058

ESP6500AA AF: 0.110 AC: 483

ESP6500EA AF: 0.525 AC: 4514

ExAC AF: 0.411 AC: 49863

Asia WGS AF: 0.210 AC: 733 AN: 3478

EpiCase AF: 0.536

EpiControl AF: 0.537

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Alpha-methylacyl-CoA racemase deficiency Benign:4

Mar 06, 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. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:3

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Jul 18, 2017

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 06, 2016

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. -

not provided Benign:2

Oct 22, 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

- -

Congenital bile acid synthesis defect 4 Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T;.;.;T;T
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.72	T;T;T;T;T
MetaRNN	Benign	0.0040	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.9	H;H;.;.;.
PhyloP100		4.5
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-4.8	D;D;D;.;.
REVEL	Uncertain	0.57
Sift	Benign	0.049	D;D;D;.;.
Sift4G	Uncertain	0.0060	D;D;D;D;D
Polyphen		0.93	P;.;P;.;.
Vest4		0.27
MPC		0.24
ClinPred		0.099	T
GERP RS		5.9
Varity_R		0.68
gMVP		0.89
Mutation Taster		=7/93	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs10941112; hg19: chr5-34004707; COSMIC: COSV59461134;