rs121917814

Variant names:

• chr5-34007866-A-G
• rs121917814
• NM_014324.6:c.154T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 9P and 1B. PP3 PP5_Very_Strong BP4

The NM_014324.6(AMACR):​c.154T>C​(p.Ser52Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000836 in 1,589,586 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00044 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00088 (0 hom.)
• Consequence: AMACR NM_014324.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 6.12
• Publications: 19 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: Likely_pathogenic. The variant received 8 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 10: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, M_CAP, MutationAssessor, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• PP5: Variant 5-34007866-A-G is Pathogenic according to our data. Variant chr5-34007866-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 5523.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.37628245). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AMACR	NM_014324.6	c.154T>C	p.Ser52Pro	missense_variant	Exon 1 of 5	ENST00000335606.11	NP_055139.4
AMACR	NM_001167595.2	c.154T>C	p.Ser52Pro	missense_variant	Exon 1 of 6		NP_001161067.1
AMACR	NM_203382.3	c.154T>C	p.Ser52Pro	missense_variant	Exon 1 of 4		NP_976316.1
C1QTNF3-AMACR	NR_037951.1	n.765-1967T>C		intron_variant	Intron 6 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AMACR	ENST00000335606.11	c.154T>C	p.Ser52Pro	missense_variant	Exon 1 of 5	1	NM_014324.6	ENSP00000334424.6
ENSG00000289791	ENST00000426255.6	c.154T>C	p.Ser52Pro	missense_variant	Exon 1 of 5	2		ENSP00000476965.1
C1QTNF3-AMACR	ENST00000382079.3	n.690-1967T>C		intron_variant	Intron 6 of 8	2		ENSP00000371511.3

Frequencies

GnomAD3 genomes AF: 0.000440 AC: 67 AN: 152132 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000343 AC: 66 AN: 192498 AF XY: 0.000307

Gnomad AFR exome AF: 0.000577

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000150

Gnomad NFE exome AF: 0.000720

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000878 AC: 1262 AN: 1437454 Hom.: 0 Cov.: 31 AF XY: 0.000891 AC XY: 636 AN XY: 713900

African (AFR) AF: 0.000181 AC: 6 AN: 33084

American (AMR) AF: 0.00 AC: 0 AN: 41930

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25764

East Asian (EAS) AF: 0.00 AC: 0 AN: 38758

South Asian (SAS) AF: 0.00 AC: 0 AN: 84730

European-Finnish (FIN) AF: 0.000374 AC: 17 AN: 45398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.00110 AC: 1217 AN: 1102510

Other (OTH) AF: 0.000370 AC: 22 AN: 59538

GnomAD4 genome AF: 0.000440 AC: 67 AN: 152132 Hom.: 0 Cov.: 32 AF XY: 0.000283 AC XY: 21 AN XY: 74314

African (AFR) AF: 0.000410 AC: 17 AN: 41440

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000735 AC: 50 AN: 68000

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000675 Hom.: 0

Bravo AF: 0.000400

ExAC AF: 0.000240 AC: 28

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Alpha-methylacyl-CoA racemase deficiency Pathogenic:5

Jun 23, 2022

MGZ Medical Genetics Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 17, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Sep 25, 2017

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The AMACR c.154T>C (p.Ser52Pro) missense variant has been reported in a homozygous state in seven unrelated patients with alpha-methylacyl-CoA racemase deficiency, including six with adolescent or adult-onset symptoms and one infant with a severe congenital bile synthesis defect (Ferdinandusse et al. 2000; Setchell et. at. 2003; Clarke et al. 2004; Thompson et al. 2008; Smith et al. 2010; Dick et al. 2011). Four of these patients demonstrated absence of AMACR activity in cultured skin fibroblasts (Ferdinandusse et al. 2000; Clark et al. 2004; Thompson et al. 2008). The p.Ser52Pro variant was absent from 114 control alleles but is reported at a frequency of 0.001343 in the African population of the Exome Aggregation Consortium. The recombinant p.Ser52Pro variant protein expressed in E.coli was inactive (Ferdinandusse et al. 2000). Based on the evidence, the p.Ser52Pro variant is classified as pathogenic for alpha-methylacyl-CoA racemase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 52 of the AMACR protein (p.Ser52Pro). This variant is present in population databases (rs121917814, gnomAD 0.07%). This missense change has been observed in individuals with alpha-methylacyl-CoA racemase deficiency (PMID: 10655068, 20821052, 21576695, 21686617, 30369941). ClinVar contains an entry for this variant (Variation ID: 5523). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt AMACR protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects AMACR function (PMID: 10655068). For these reasons, this variant has been classified as Pathogenic. -

Jul 28, 2023

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ser52Pro variant in AMACR has been reported in at least 7 homozygous individuals with alpha-methylacyl-CoA racemase deficiency, including six with adolescent or adult-onset symptoms and one infant with a severe congenital bile synthesis defect (selected publications: Ferdinandusse 2000 PMID: 10655068, Setchell 2003 PMID: 12512044, Clarke 2004 PMID: 15249642, Thompson 2008 PMID: 18032455, Smith 2010 PMID: 20821052, Dick 2011 PMID: 21576695). This variant has also been identified in 0.07% (50/68000) European chromosomes by gnomAD v3.1.2 (https://gnomad.broadinstitute.org/) and has been reported in ClinVar (Variation ID 5523). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In vitro functional studies, including using skin fibroblasts from patients, support an impact on protein function (Ferdinandusse 2000 PMID: 10655068, Clarke 2004 PMID: 15249642, Thompson 2008 PMID: 18032455). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive alpha-methylacyl-CoA racemase deficiency. ACMG/AMP criteria applied: PM3, PS3 -

not provided Pathogenic:3

Sep 22, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 15, 2018

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 27, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate an undetectable residual enzyme activity compared to wild-type (Ferdinandusse et al., 2000); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20821052, 15249642, 18032455, 10655068, 12512044, 23286897, 21576695, 31589614, 35641312, 30369941, 33047465, 21686617, 34732400) -

AMACR-related disorder Pathogenic:1

Feb 12, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The AMACR c.154T>C variant is predicted to result in the amino acid substitution p.Ser52Pro. This variant has been reported in the homozygous state in multiple individuals with α-methylacyl-CoA racemase deficiency (Ferdinandusse et al. 2000. PubMed ID: 10655068; Smith et al. 2010. PubMed ID: 20821052), an individual with autosomal recessive cerebellar ataxia (Dick et al. 2011. PubMed ID: 21576695), and an individual with leigh-like, optic atrophy, and exercise intolerance (Theunissen et al. 2018. PubMed ID: 30369941). Functional in vitro studies showed that this variant negatively affects enzyme activity (Ferdinandusse et al. 2000. PubMed ID: 10655068). This variant is reported in 0.071% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Inborn genetic diseases Pathogenic:1

May 25, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.154T>C (p.S52P) alteration is located in exon 1 (coding exon 1) of the AMACR gene. This alteration results from a T to C substitution at nucleotide position 154, causing the serine (S) at amino acid position 52 to be replaced by a proline (P). Based on data from the Genome Aggregation Database (gnomAD) database, the AMACR c.154T>C alteration was observed in 0.04% (79/223800) of total alleles studied, with a frequency of 0.07% (68/95942) in the European (non-Finnish) subpopulation. This mutation has been reported in the homozygous state in multiple unrelated patients with clinical and biochemical features of alpha-methylacyl-CoA racemase deficiency (Ferdinandusse, 2000; Clarke, 2004; Thompson, 2009; Smith, 2010; Dick, 2011; Theunissen, 2018). This amino acid position is highly conserved in available vertebrate species. Patient fibroblasts showed absent AMACR activity and in vitro functional studies demonstrated that the p.S52P mutation results in an inactive protein (Ferdinandusse, 2000). The p.S52P alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Congenital bile acid synthesis defect 4 Pathogenic:1

May 17, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D;.;.;.;T;T;T
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D;D
M_CAP	Pathogenic	0.54	D
MetaRNN	Benign	0.38	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.44	D
MutationAssessor	Pathogenic	4.2	H;H;H;.;.;.;.
PhyloP100		6.1
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-4.6	D;D;D;D;.;.;.
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0020	D;D;D;D;.;.;.
Sift4G	Uncertain	0.0030	D;D;D;D;D;D;D
Polyphen		1.0	D;D;.;D;.;.;.
Vest4		0.51
MVP		0.85
MPC		2.1
ClinPred		0.67	D
GERP RS		5.0
PromoterAI		0.012	Neutral
Varity_R		0.98
gMVP		0.90
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121917814; hg19: chr5-34007971;