5-33998778-A-G

Variant names:

• chr5-33998778-A-G
• rs2287939
• NM_014324.6:c.602T>C

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.602T>C​(p.Leu201Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.708 in 1,613,612 control chromosomes in the GnomAD database, including 408,251 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L201W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.74 (41522 hom., cov: 31)
  • Exomes 𝑓: 0.71 (366729 hom.)
• Consequence: AMACR NM_014324.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.718
• Publications: 51 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=1.1085564E-6).
• BP6: Variant 5-33998778-A-G is Benign according to our data. Variant chr5-33998778-A-G is described in ClinVar as Benign. ClinVar VariationId is 128358.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.817 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014324.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AMACR	NM_014324.6	MANE Select	c.602T>C	p.Leu201Ser	missense	Exon 4 of 5	NP_055139.4
	AMACR	NM_001167595.2		c.602T>C	p.Leu201Ser	missense	Exon 4 of 6	NP_001161067.1
	AMACR	NM_203382.3		c.441T>C	p.Ile147Ile	synonymous	Exon 3 of 4	NP_976316.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AMACR	ENST00000335606.11	TSL:1 MANE Select	c.602T>C	p.Leu201Ser	missense	Exon 4 of 5	ENSP00000334424.6
	AMACR	ENST00000382085.7	TSL:1	c.602T>C	p.Leu201Ser	missense	Exon 4 of 6	ENSP00000371517.3
	ENSG00000289791	ENST00000426255.6	TSL:2	c.602T>C	p.Leu201Ser	missense	Exon 4 of 5	ENSP00000476965.1

Frequencies

GnomAD3 genomes AF: 0.736 AC: 111701 AN: 151842 Hom.: 41481 Cov.: 31

Gnomad AFR AF: 0.811

Gnomad AMI AF: 0.676

Gnomad AMR AF: 0.715

Gnomad ASJ AF: 0.760

Gnomad EAS AF: 0.838

Gnomad SAS AF: 0.497

Gnomad FIN AF: 0.723

Gnomad MID AF: 0.639

Gnomad NFE AF: 0.706

Gnomad OTH AF: 0.719

GnomAD2 exomes AF: 0.703 AC: 176769 AN: 251432 AF XY: 0.688

Gnomad AFR exome AF: 0.819

Gnomad AMR exome AF: 0.736

Gnomad ASJ exome AF: 0.752

Gnomad EAS exome AF: 0.826

Gnomad FIN exome AF: 0.728

Gnomad NFE exome AF: 0.705

Gnomad OTH exome AF: 0.706

GnomAD4 exome AF: 0.706 AC: 1031224 AN: 1461650 Hom.: 366729 Cov.: 53 AF XY: 0.699 AC XY: 508070 AN XY: 727152

African (AFR) AF: 0.811 AC: 27158 AN: 33476

American (AMR) AF: 0.729 AC: 32613 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.754 AC: 19696 AN: 26132

East Asian (EAS) AF: 0.856 AC: 33989 AN: 39696

South Asian (SAS) AF: 0.501 AC: 43178 AN: 86254

European-Finnish (FIN) AF: 0.734 AC: 39186 AN: 53414

Middle Eastern (MID) AF: 0.639 AC: 3688 AN: 5768

European-Non Finnish (NFE) AF: 0.710 AC: 789209 AN: 1111818

Other (OTH) AF: 0.704 AC: 42507 AN: 60374

GnomAD4 genome AF: 0.736 AC: 111792 AN: 151962 Hom.: 41522 Cov.: 31 AF XY: 0.733 AC XY: 54448 AN XY: 74262

African (AFR) AF: 0.811 AC: 33616 AN: 41428

American (AMR) AF: 0.715 AC: 10904 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.760 AC: 2637 AN: 3470

East Asian (EAS) AF: 0.838 AC: 4334 AN: 5174

South Asian (SAS) AF: 0.497 AC: 2394 AN: 4818

European-Finnish (FIN) AF: 0.723 AC: 7643 AN: 10564

Middle Eastern (MID) AF: 0.636 AC: 187 AN: 294

European-Non Finnish (NFE) AF: 0.706 AC: 47958 AN: 67948

Other (OTH) AF: 0.714 AC: 1505 AN: 2108

Alfa AF: 0.715 Hom.: 179518

Bravo AF: 0.746

TwinsUK AF: 0.712 AC: 2640

ALSPAC AF: 0.712 AC: 2743

ESP6500AA AF: 0.817 AC: 3598

ESP6500EA AF: 0.714 AC: 6139

ExAC AF: 0.699 AC: 84904

Asia WGS AF: 0.623 AC: 2167 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Alpha-methylacyl-CoA racemase deficiency Benign:3

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.

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:2

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.

Dec 23, 2015

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.0040
DANN	Benign	0.37
DEOGEN2	Benign	0.098	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.058	T
MetaRNN	Benign	0.0000011	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.47	N
PhyloP100		-0.72
PrimateAI	Benign	0.23	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.077
Sift	Benign	0.44	T
Sift4G	Benign	0.69	T
Polyphen		0.0010	B
Vest4		0.11
MPC		0.072
ClinPred		0.0099	T
GERP RS		-6.1
Varity_R		0.050
gMVP		0.70
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs2287939; hg19: chr5-33998883; COSMIC: COSV59461114; COSMIC: COSV59461114;