rs140021599

Positions:

• chr5-33988340-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001167595.2(AMACR):​c.1153T>G​(p.Leu385Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00125 in 1,541,968 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0066 (10 hom., cov: 32)
  • Exomes 𝑓: 0.00067 (18 hom.)
• Consequence: AMACR NM_001167595.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.59

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: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]

AMACR (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0035224557).
• BP6: Variant 5-33988340-A-C is Benign according to our data. Variant chr5-33988340-A-C is described in ClinVar as [Benign]. Clinvar id is 353242.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-33988340-A-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00655 (998/152286) while in subpopulation AFR AF= 0.0231 (960/41552). AF 95% confidence interval is 0.0219. There are 10 homozygotes in gnomad4. There are 493 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AMACR	NM_014324.6	c.*753T>G		3_prime_UTR_variant	5/5	ENST00000335606.11	NP_055139.4
AMACR	NM_001167595.2	c.1153T>G	p.Leu385Val	missense_variant	6/6		NP_001161067.1
AMACR	NM_203382.3	c.*1144T>G		3_prime_UTR_variant	4/4		NP_976316.1
C1QTNF3-AMACR	NR_037951.1	n.2258T>G		non_coding_transcript_exon_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AMACR	ENST00000335606	c.*753T>G		3_prime_UTR_variant	5/5	1	NM_014324.6	ENSP00000334424.6
C1QTNF3-AMACR	ENST00000382079.3	n.*1328T>G		non_coding_transcript_exon_variant	9/9	2		ENSP00000371511.3
C1QTNF3-AMACR	ENST00000382079.3	n.*1328T>G		3_prime_UTR_variant	9/9	2		ENSP00000371511.3

Frequencies

GnomAD3 genomes AF: 0.00652 AC: 992 AN: 152168 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.0230

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00716

GnomAD3 exomes AF: 0.00138 AC: 210 AN: 152046 Hom.: 2 AF XY: 0.00111 AC XY: 90 AN XY: 80984

Gnomad AFR exome AF: 0.0214

Gnomad AMR exome AF: 0.000879

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000880

Gnomad SAS exome AF: 0.0000870

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000469

Gnomad OTH exome AF: 0.000450

GnomAD4 exome AF: 0.000669 AC: 930 AN: 1389682 Hom.: 18 Cov.: 29 AF XY: 0.000567 AC XY: 389 AN XY: 686136

Gnomad4 AFR exome AF: 0.0229

Gnomad4 AMR exome AF: 0.00116

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000138

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000305

Gnomad4 OTH exome AF: 0.00174

GnomAD4 genome AF: 0.00655 AC: 998 AN: 152286 Hom.: 10 Cov.: 32 AF XY: 0.00662 AC XY: 493 AN XY: 74476

Gnomad4 AFR AF: 0.0231

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00709

Alfa AF: 0.00118 Hom.: 3

Bravo AF: 0.00713

ESP6500AA AF: 0.0206 AC: 64

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00112 AC: 123

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 12, 2017	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 01, 2016	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Alpha-methylacyl-CoA racemase deficiency Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	8.5
DANN	Benign	0.82
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.060	N
LIST_S2	Benign	0.29	T
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.030	N
REVEL	Benign	0.057
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.27	T
Vest4		0.21
MVP		0.32
MPC		0.058
ClinPred		0.039	T
GERP RS		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs140021599; hg19: chr5-33988445;