rs15612

Variant names:

• chr5-33988430-C-T
• rs15612
• ENST00000382079.3:n.*1238G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000382079.3(C1QTNF3-AMACR):​n.*1238G>A variant causes a non coding transcript exon 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: C1QTNF3-AMACR ENST00000382079.3 non_coding_transcript_exon
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.53
• Publications: 12 publications found

Genes affected

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: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]

AMACR Gene-Disease associations (from GenCC):

• alpha-methylacyl-CoA racemase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, G2P
• congenital bile acid synthesis defect 4

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000382079.3. 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.*663G>A		3_prime_UTR	Exon 5 of 5	NP_055139.4
	C1QTNF3-AMACR	NR_037951.1		n.2168G>A		non_coding_transcript_exon	Exon 9 of 9
	AMACR	NM_203382.3		c.*1054G>A		3_prime_UTR	Exon 4 of 4	NP_976316.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C1QTNF3-AMACR	ENST00000382079.3	TSL:2	n.*1238G>A		non_coding_transcript_exon	Exon 9 of 9	ENSP00000371511.3
	AMACR	ENST00000506639.5	TSL:1	n.*1134G>A		non_coding_transcript_exon	Exon 5 of 5	ENSP00000427227.1
	AMACR	ENST00000514195.1	TSL:1	n.1706G>A		non_coding_transcript_exon	Exon 5 of 5

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

African (AFR) AF: 0.0615 AC: 1940 AN: 31548

American (AMR) AF: 0.237 AC: 8456 AN: 35644

Ashkenazi Jewish (ASJ) AF: 0.331 AC: 8301 AN: 25100

East Asian (EAS) AF: 0.0414 AC: 1478 AN: 35688

South Asian (SAS) AF: 0.415 AC: 32725 AN: 78898

European-Finnish (FIN) AF: 0.274 AC: 9527 AN: 34782

Middle Eastern (MID) AF: 0.430 AC: 2414 AN: 5608

European-Non Finnish (NFE) AF: 0.294 AC: 316335 AN: 1077716

Other (OTH) AF: 0.283 AC: 16345 AN: 57788

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

African (AFR) AF: 0.0649 AC: 2693 AN: 41508

American (AMR) AF: 0.255 AC: 3904 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.334 AC: 1161 AN: 3472

East Asian (EAS) AF: 0.0402 AC: 208 AN: 5176

South Asian (SAS) AF: 0.392 AC: 1885 AN: 4810

European-Finnish (FIN) AF: 0.290 AC: 3058 AN: 10542

Middle Eastern (MID) AF: 0.412 AC: 121 AN: 294

European-Non Finnish (NFE) AF: 0.297 AC: 20187 AN: 67972

Other (OTH) AF: 0.244 AC: 513 AN: 2106

Alfa AF: 0.276 Hom.: 5202

Bravo AF: 0.209

Asia WGS AF: 0.196 AC: 682 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Alpha-methylacyl-CoA racemase deficiency (2)
-	-	2	not provided (2)
-	-	1	Congenital bile acid synthesis defect 4 (1)
-	-	1	Oculocutaneous albinism (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.17
DANN	Benign	0.49
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs15612; hg19: chr5-33988535;