5-33998778-A-G

Position:

• chr5-33998778-A-G

Variant summary

Our verdict is Benign. Variant got -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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin 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:7
• Conservation: PhyloP100: -0.718

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]

C1QTNF3-AMACR (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id is 128358.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-33998778-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.817 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AMACR	NM_014324.6	c.602T>C	p.Leu201Ser	missense_variant	4/5	ENST00000335606.11
C1QTNF3-AMACR	NR_037951.1	n.958T>C		non_coding_transcript_exon_variant	8/9
AMACR	NM_001167595.2	c.602T>C	p.Leu201Ser	missense_variant	4/6
AMACR	NM_203382.3	c.441T>C	p.Ile147=	synonymous_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AMACR	ENST00000335606.11	c.602T>C	p.Leu201Ser	missense_variant	4/5	1	NM_014324.6	P1

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

GnomAD3 exomes AF: 0.703 AC: 176769 AN: 251432 Hom.: 63175 AF XY: 0.688 AC XY: 93500 AN XY: 135876

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 SAS exome AF: 0.491

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

Gnomad4 AFR exome AF: 0.811

Gnomad4 AMR exome AF: 0.729

Gnomad4 ASJ exome AF: 0.754

Gnomad4 EAS exome AF: 0.856

Gnomad4 SAS exome AF: 0.501

Gnomad4 FIN exome AF: 0.734

Gnomad4 NFE exome AF: 0.710

Gnomad4 OTH exome AF: 0.704

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

Gnomad4 AFR AF: 0.811

Gnomad4 AMR AF: 0.715

Gnomad4 ASJ AF: 0.760

Gnomad4 EAS AF: 0.838

Gnomad4 SAS AF: 0.497

Gnomad4 FIN AF: 0.723

Gnomad4 NFE AF: 0.706

Gnomad4 OTH AF: 0.714

Alfa AF: 0.711 Hom.: 90541

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:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Alpha-methylacyl-CoA racemase deficiency Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	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. -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 23, 2015	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. -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -

Congenital bile acid synthesis defect 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

not provided Benign:1

Benign, no assertion criteria provided

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Oct 22, 2015

- -

Computational scores

Source: dbNSFP v4.3

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;.;.;T;T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.058	T;T;T;T;T
MetaRNN	Benign	0.0000011	T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.47	N;N;.;.;.
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.23	T
PROVEAN	Uncertain	-2.6	D;D;N;.;.
REVEL	Benign	0.077
Sift	Benign	0.44	T;T;T;.;.
Sift4G	Benign	0.69	T;T;T;T;T
Polyphen		0.0010	B;.;B;.;.
Vest4		0.11
MPC		0.072
ClinPred		0.0099	T
GERP RS		-6.1
Varity_R		0.050
gMVP		0.70

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

Publications

LitVar

Other links and lift over

dbSNP: rs2287939; hg19: chr5-33998883; COSMIC: COSV59461114; COSMIC: COSV59461114;