rs15612

Variant names:

• chr5-33988430-C-T
• rs15612
• NM_014324.6:c.*663G>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.*663G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.281 in 1,534,846 control chromosomes in the GnomAD database, including 64,891 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4840 hom., cov: 32)
  • Exomes 𝑓: 0.29 (60051 hom.)
• Consequence: AMACR NM_014324.6 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.53

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 5-33988430-C-T is Benign according to our data. Variant chr5-33988430-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 353244.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.377 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AMACR	NM_014324.6	c.*663G>A		3_prime_UTR_variant	Exon 5 of 5	ENST00000335606.11	NP_055139.4
AMACR	NM_203382.3	c.*1054G>A		3_prime_UTR_variant	Exon 4 of 4		NP_976316.1
AMACR	NM_001167595.2	c.1132-69G>A		intron_variant	Intron 5 of 5		NP_001161067.1
C1QTNF3-AMACR	NR_037951.1	n.2168G>A		non_coding_transcript_exon_variant	Exon 9 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AMACR	ENST00000335606	c.*663G>A		3_prime_UTR_variant	Exon 5 of 5	1	NM_014324.6	ENSP00000334424.6
C1QTNF3-AMACR	ENST00000382079.3	n.*1238G>A		non_coding_transcript_exon_variant	Exon 9 of 9	2		ENSP00000371511.3
C1QTNF3-AMACR	ENST00000382079.3	n.*1238G>A		3_prime_UTR_variant	Exon 9 of 9	2		ENSP00000371511.3

Frequencies

GnomAD3 genomes AF: 0.224 AC: 34033 AN: 151956 Hom.: 4838 Cov.: 32

Gnomad AFR AF: 0.0650

Gnomad AMI AF: 0.326

Gnomad AMR AF: 0.256

Gnomad ASJ AF: 0.334

Gnomad EAS AF: 0.0401

Gnomad SAS AF: 0.391

Gnomad FIN AF: 0.290

Gnomad MID AF: 0.408

Gnomad NFE AF: 0.297

Gnomad OTH AF: 0.244

GnomAD4 exome AF: 0.287 AC: 397521 AN: 1382772 Hom.: 60051 Cov.: 32 AF XY: 0.293 AC XY: 200016 AN XY: 682344

Gnomad4 AFR exome AF: 0.0615

Gnomad4 AMR exome AF: 0.237

Gnomad4 ASJ exome AF: 0.331

Gnomad4 EAS exome AF: 0.0414

Gnomad4 SAS exome AF: 0.415

Gnomad4 FIN exome AF: 0.274

Gnomad4 NFE exome AF: 0.294

Gnomad4 OTH exome AF: 0.283

GnomAD4 genome AF: 0.224 AC: 34027 AN: 152074 Hom.: 4840 Cov.: 32 AF XY: 0.225 AC XY: 16715 AN XY: 74334

Gnomad4 AFR AF: 0.0649

Gnomad4 AMR AF: 0.255

Gnomad4 ASJ AF: 0.334

Gnomad4 EAS AF: 0.0402

Gnomad4 SAS AF: 0.392

Gnomad4 FIN AF: 0.290

Gnomad4 NFE AF: 0.297

Gnomad4 OTH AF: 0.244

Alfa AF: 0.283 Hom.: 3961

Bravo AF: 0.209

Asia WGS AF: 0.196 AC: 682 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 29, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Alpha-methylacyl-CoA racemase deficiency Benign:2

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oculocutaneous albinism Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.17
DANN	Benign	0.49

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: rs15612; hg19: chr5-33988535;