rs34677

chr5-33998663-C-A

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.717G>T(p.Gln239His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.136 in 1,610,232 control chromosomes in the GnomAD database, including 15,506 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1072 hom., cov: 31)
  • Exomes 𝑓: 0.14 (14434 hom.)
• Consequence: AMACR NM_014324.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.90

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=0.0025598407).
• BP6: Variant 5-33998663-C-A is Benign according to our data. Variant chr5-33998663-C-A is described in ClinVar as [Benign]. Clinvar id is 128359.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.157 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AMACR	NM_014324.6	c.717G>T	p.Gln239His	missense_variant	4/5	ENST00000335606.11
C1QTNF3-AMACR	NR_037951.1	n.1073G>T		non_coding_transcript_exon_variant	8/9
AMACR	NM_001167595.2	c.717G>T	p.Gln239His	missense_variant	4/6
AMACR	NM_203382.3	c.556G>T	p.Val186Phe	missense_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AMACR	ENST00000335606.11	c.717G>T	p.Gln239His	missense_variant	4/5	1	NM_014324.6	P1

Frequencies

GnomAD3 genomes AF: 0.115 AC: 17400 AN: 151846 Hom.: 1073 Cov.: 31

Gnomad AFR AF: 0.0629

Gnomad AMI AF: 0.117

Gnomad AMR AF: 0.0830

Gnomad ASJ AF: 0.161

Gnomad EAS AF: 0.166

Gnomad SAS AF: 0.141

Gnomad FIN AF: 0.155

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.139

Gnomad OTH AF: 0.112

GnomAD3 exomes AF: 0.127 AC: 31792 AN: 250114 Hom.: 2274 AF XY: 0.132 AC XY: 17799 AN XY: 135166

Gnomad AFR exome AF: 0.0607

Gnomad AMR exome AF: 0.0581

Gnomad ASJ exome AF: 0.155

Gnomad EAS exome AF: 0.177

Gnomad SAS exome AF: 0.142

Gnomad FIN exome AF: 0.164

Gnomad NFE exome AF: 0.135

Gnomad OTH exome AF: 0.145

GnomAD4 exome AF: 0.138 AC: 200939 AN: 1458268 Hom.: 14434 Cov.: 31 AF XY: 0.139 AC XY: 100396 AN XY: 724822

Gnomad4 AFR exome AF: 0.0657

Gnomad4 AMR exome AF: 0.0627

Gnomad4 ASJ exome AF: 0.158

Gnomad4 EAS exome AF: 0.131

Gnomad4 SAS exome AF: 0.145

Gnomad4 FIN exome AF: 0.158

Gnomad4 NFE exome AF: 0.141

Gnomad4 OTH exome AF: 0.143

GnomAD4 genome AF: 0.114 AC: 17394 AN: 151964 Hom.: 1072 Cov.: 31 AF XY: 0.116 AC XY: 8611 AN XY: 74262

Gnomad4 AFR AF: 0.0628

Gnomad4 AMR AF: 0.0829

Gnomad4 ASJ AF: 0.161

Gnomad4 EAS AF: 0.166

Gnomad4 SAS AF: 0.141

Gnomad4 FIN AF: 0.155

Gnomad4 NFE AF: 0.139

Gnomad4 OTH AF: 0.109

Alfa AF: 0.134 Hom.: 3656

Bravo AF: 0.107

TwinsUK AF: 0.139 AC: 517

ALSPAC AF: 0.142 AC: 549

ESP6500AA AF: 0.0704 AC: 310

ESP6500EA AF: 0.145 AC: 1250

ExAC AF: 0.126 AC: 15348

Asia WGS AF: 0.131 AC: 457 AN: 3478

EpiCase AF: 0.138

EpiControl AF: 0.133

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 17, 2018	- -
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. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 21, 2016	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. -
Benign, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Benign - Stand Alone. The following ACMG Tag(s) were applied: BA1 => Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. -

Alpha-methylacyl-CoA racemase deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

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	0.31
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	19
Dann	Uncertain	0.98
DEOGEN2	Benign	0.21	T;.;.;T;T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.97	D;D;D;D;D
MetaRNN	Benign	0.0026	T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.6	L;L;.;.;.
MutationTaster	Benign	0.98	P;P;P;P;P
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-3.9	D;D;D;.;.
REVEL	Benign	0.18
Sift	Uncertain	0.027	D;D;D;.;.
Sift4G	Uncertain	0.054	T;D;T;D;T
Polyphen		0.70	P;.;P;.;.
Vest4		0.28
MutPred		0.64		Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);.;Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);
MPC		0.072
ClinPred		0.013	T
GERP RS		3.3
Varity_R		0.56
gMVP		0.68

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

Other links and lift over

dbSNP: rs34677; hg19: chr5-33998768; COSMIC: COSV59460034; COSMIC: COSV59460034;