rs840380

Variant names:

• chr5-33987949-T-C
• rs840380
• NM_014324.6:c.*1144A>G

Variant summary

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

The NM_014324.6(AMACR):​c.*1144A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.03 in 169,432 control chromosomes in the GnomAD database, including 239 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (206 hom., cov: 33)
  • Exomes 𝑓: 0.037 (33 hom.)
• Consequence: AMACR NM_014324.6 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.402
• Publications: 4 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 5-33987949-T-C is Benign according to our data. Variant chr5-33987949-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 353237.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.155 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014324.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AMACR	NM_014324.6	MANE Select	c.*1144A>G		3_prime_UTR	Exon 5 of 5	NP_055139.4
	AMACR	NM_001167595.2		c.*359A>G		3_prime_UTR	Exon 6 of 6	NP_001161067.1	Q9UHK6-5
	AMACR	NM_203382.3		c.*1535A>G		3_prime_UTR	Exon 4 of 4	NP_976316.1	Q9UHK6-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AMACR	ENST00000335606.11	TSL:1 MANE Select	c.*1144A>G		3_prime_UTR	Exon 5 of 5	ENSP00000334424.6	Q9UHK6-1
	AMACR	ENST00000382072.6	TSL:1	c.*1535A>G		3_prime_UTR	Exon 4 of 4	ENSP00000371504.2	Q9UHK6-4
	C1QTNF3-AMACR	ENST00000382079.3	TSL:2	n.*1719A>G		non_coding_transcript_exon	Exon 9 of 9	ENSP00000371511.3	E9PGA6

Frequencies

GnomAD3 genomes AF: 0.0292 AC: 4437 AN: 152190 Hom.: 199 Cov.: 33

Gnomad AFR AF: 0.00644

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0863

Gnomad ASJ AF: 0.0164

Gnomad EAS AF: 0.164

Gnomad SAS AF: 0.107

Gnomad FIN AF: 0.00320

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0186

Gnomad OTH AF: 0.0559

GnomAD4 exome AF: 0.0368 AC: 630 AN: 17126 Hom.: 33 Cov.: 0 AF XY: 0.0349 AC XY: 301 AN XY: 8616

African (AFR) AF: 0.00435 AC: 3 AN: 690

American (AMR) AF: 0.136 AC: 75 AN: 552

Ashkenazi Jewish (ASJ) AF: 0.0227 AC: 18 AN: 792

East Asian (EAS) AF: 0.179 AC: 196 AN: 1098

South Asian (SAS) AF: 0.129 AC: 23 AN: 178

European-Finnish (FIN) AF: 0.00502 AC: 3 AN: 598

Middle Eastern (MID) AF: 0.0909 AC: 8 AN: 88

European-Non Finnish (NFE) AF: 0.0206 AC: 244 AN: 11872

Other (OTH) AF: 0.0477 AC: 60 AN: 1258

GnomAD4 genome AF: 0.0292 AC: 4449 AN: 152306 Hom.: 206 Cov.: 33 AF XY: 0.0314 AC XY: 2342 AN XY: 74482

African (AFR) AF: 0.00645 AC: 268 AN: 41574

American (AMR) AF: 0.0872 AC: 1334 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0164 AC: 57 AN: 3470

East Asian (EAS) AF: 0.164 AC: 849 AN: 5176

South Asian (SAS) AF: 0.106 AC: 511 AN: 4814

European-Finnish (FIN) AF: 0.00320 AC: 34 AN: 10630

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0186 AC: 1267 AN: 68022

Other (OTH) AF: 0.0558 AC: 118 AN: 2114

Alfa AF: 0.0297 Hom.: 201

Bravo AF: 0.0370

Asia WGS AF: 0.113 AC: 393 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Alpha-methylacyl-CoA racemase deficiency (1)
-	-	1	not provided (1)
-	-	1	Oculocutaneous albinism (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.79
DANN	Benign	0.35
PhyloP100		-0.40
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: rs840380; hg19: chr5-33988054;