rs121917814

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 11P and 1B. PM2PP3PP5_Very_StrongBP4

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

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 6.12

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 Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, M_CAP, MutationAssessor, PROVEAN, REVEL [when 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 [Likely_pathogenic]. Clinvar id 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/exons	MANE
AMACR	NM_014324.6 linkuse as main transcript	c.154T>C	p.Ser52Pro	missense_variant	1/5	ENST00000335606.11
C1QTNF3-AMACR	NR_037951.1 linkuse as main transcript	n.765-1967T>C		intron_variant, non_coding_transcript_variant
AMACR	NM_001167595.2 linkuse as main transcript	c.154T>C	p.Ser52Pro	missense_variant	1/6
AMACR	NM_203382.3 linkuse as main transcript	c.154T>C	p.Ser52Pro	missense_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AMACR	ENST00000335606.11 linkuse as main transcript	c.154T>C	p.Ser52Pro	missense_variant	1/5	1	NM_014324.6	P1	Q9UHK6-1

Frequencies

GnomAD3 genomes

AF:

0.000440

AC:

AN:

152132

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.000343

AC:

AN:

192498

Hom.:

AF XY:

0.000307

AC XY:

AN XY:

107526

show subpopulations

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 SAS 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.:

Cov.:

AF XY:

0.000891

AC XY:

636

AN XY:

713900

show subpopulations

Gnomad4 AFR exome

AF:

0.000181

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000374

Gnomad4 NFE exome

AF:

0.00110

Gnomad4 OTH exome

AF:

0.000370

GnomAD4 genome

AF:

0.000440

AC:

AN:

152132

Hom.:

Cov.:

AF XY:

0.000283

AC XY:

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.000410

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000651

Hom.:

Bravo

AF:

0.000400

ExAC

AF:

0.000240

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Alpha-methylacyl-CoA racemase deficiency

Pathogenic:5

Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jun 23, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 17, 2011	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Sep 25, 2017	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 28, 2023	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

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 22, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 27, 2023	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 15, 2018	- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 25, 2021

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

Pathogenic, no assertion criteria provided

literature only

OMIM

May 17, 2011

- -

AMACR-related condition

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 12, 2024

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.40

Cadd

Pathogenic

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

LIST_S2

Uncertain

0.91

D;D;D;D;D;D;D

M_CAP

Pathogenic

0.54

MetaRNN

Benign

0.38

T;T;T;T;T;T;T

MetaSVM

Uncertain

0.44

MutationAssessor

Pathogenic

4.2

H;H;H;.;.;.;.

MutationTaster

Benign

1.0

A;A;A;A;A

PrimateAI

Uncertain

0.72

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

GERP RS

5.0

Varity_R

0.98

gMVP

0.90

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