rs16892096

Variant names:

• chr5-33994077-T-C
• rs16892096
• ENST00000506639.5:n.622A>G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 1P and 8B. PP3 BA1

The ENST00000335606.11(AMACR):​c.739+4564A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0592 in 455,968 control chromosomes in the GnomAD database, including 1,888 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.051 (368 hom., cov: 32)
  • Exomes 𝑓: 0.063 (1520 hom.)
• Consequence: AMACR ENST00000335606.11 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.247
• Publications: 5 publications found

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

Our verdict: Benign. The variant received -7 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.207 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000335606.11. 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.739+4564A>G		intron	N/A	NP_055139.4
	AMACR	NM_001167595.2		c.739+4564A>G		intron	N/A	NP_001161067.1
	AMACR	NM_203382.3		c.578+4564A>G		intron	N/A	NP_976316.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AMACR	ENST00000506639.5	TSL:1	n.622A>G		non_coding_transcript_exon	Exon 4 of 5	ENSP00000427227.1
	AMACR	ENST00000335606.11	TSL:1 MANE Select	c.739+4564A>G		intron	N/A	ENSP00000334424.6
	AMACR	ENST00000382085.7	TSL:1	c.739+4564A>G		intron	N/A	ENSP00000371517.3

Frequencies

GnomAD3 genomes AF: 0.0507 AC: 7709 AN: 152144 Hom.: 360 Cov.: 32

Gnomad AFR AF: 0.0809

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0367

Gnomad ASJ AF: 0.0156

Gnomad EAS AF: 0.152

Gnomad SAS AF: 0.218

Gnomad FIN AF: 0.0295

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0216

Gnomad OTH AF: 0.0545

GnomAD2 exomes AF: 0.0687 AC: 8814 AN: 128204 AF XY: 0.0763

Gnomad AFR exome AF: 0.0736

Gnomad AMR exome AF: 0.0369

Gnomad ASJ exome AF: 0.0172

Gnomad EAS exome AF: 0.159

Gnomad FIN exome AF: 0.0275

Gnomad NFE exome AF: 0.0199

Gnomad OTH exome AF: 0.0376

GnomAD4 exome AF: 0.0635 AC: 19283 AN: 303706 Hom.: 1520 Cov.: 0 AF XY: 0.0758 AC XY: 13109 AN XY: 172916

African (AFR) AF: 0.0764 AC: 659 AN: 8622

American (AMR) AF: 0.0368 AC: 1002 AN: 27252

Ashkenazi Jewish (ASJ) AF: 0.0180 AC: 194 AN: 10788

East Asian (EAS) AF: 0.150 AC: 1380 AN: 9204

South Asian (SAS) AF: 0.193 AC: 11495 AN: 59670

European-Finnish (FIN) AF: 0.0256 AC: 317 AN: 12362

Middle Eastern (MID) AF: 0.0414 AC: 113 AN: 2728

European-Non Finnish (NFE) AF: 0.0215 AC: 3408 AN: 158870

Other (OTH) AF: 0.0503 AC: 715 AN: 14210

GnomAD4 genome AF: 0.0508 AC: 7732 AN: 152262 Hom.: 368 Cov.: 32 AF XY: 0.0546 AC XY: 4065 AN XY: 74448

African (AFR) AF: 0.0808 AC: 3358 AN: 41556

American (AMR) AF: 0.0373 AC: 571 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0156 AC: 54 AN: 3472

East Asian (EAS) AF: 0.152 AC: 787 AN: 5184

South Asian (SAS) AF: 0.218 AC: 1051 AN: 4822

European-Finnish (FIN) AF: 0.0295 AC: 313 AN: 10594

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0216 AC: 1466 AN: 68016

Other (OTH) AF: 0.0587 AC: 124 AN: 2114

Alfa AF: 0.0385 Hom.: 146

Bravo AF: 0.0487

Asia WGS AF: 0.219 AC: 759 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_noAF	Benign	-0.92
CADD	Pathogenic	27
DANN	Benign	0.64
PhyloP100		0.25
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.58		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.37		Position offset: 43
DS_DG_spliceai		0.58		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs16892096; hg19: chr5-33994182; COSMIC: COSV59461175; COSMIC: COSV59461175;