NM_014324.6:c.524G>A

Variant names:

• chr5-34004602-C-T
• rs10941112
• NM_014324.6:c.524G>A

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.524G>A​(p.Gly175Asp) variant causes a missense change. The variant allele was found at a frequency of 0.475 in 1,613,804 control chromosomes in the GnomAD database, including 196,459 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (13929 hom., cov: 32)
  • Exomes 𝑓: 0.48 (182530 hom.)
• Consequence: AMACR NM_014324.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 4.50
• Publications: 69 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]

ENSG00000289791 (HGNC:):

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 (MetaRNN=0.0040152073).
• BP6: Variant 5-34004602-C-T is Benign according to our data. Variant chr5-34004602-C-T is described in ClinVar as Benign. ClinVar VariationId is 128357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.524 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.524G>A	p.Gly175Asp	missense	Exon 3 of 5	NP_055139.4
	AMACR	NM_001167595.2		c.524G>A	p.Gly175Asp	missense	Exon 3 of 6	NP_001161067.1	Q9UHK6-5
	AMACR	NM_203382.3		c.391+1154G>A		intron	N/A	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.524G>A	p.Gly175Asp	missense	Exon 3 of 5	ENSP00000334424.6	Q9UHK6-1
	AMACR	ENST00000382085.7	TSL:1	c.524G>A	p.Gly175Asp	missense	Exon 3 of 6	ENSP00000371517.3	Q9UHK6-5
	ENSG00000289791	ENST00000426255.6	TSL:2	c.524G>A	p.Gly175Asp	missense	Exon 3 of 5	ENSP00000476965.1	V9GYP4

Frequencies

GnomAD3 genomes AF: 0.381 AC: 57872 AN: 151898 Hom.: 13930 Cov.: 32

Gnomad AFR AF: 0.0967

Gnomad AMI AF: 0.556

Gnomad AMR AF: 0.435

Gnomad ASJ AF: 0.540

Gnomad EAS AF: 0.341

Gnomad SAS AF: 0.127

Gnomad FIN AF: 0.535

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.529

Gnomad OTH AF: 0.389

GnomAD2 exomes AF: 0.420 AC: 105515 AN: 251448 AF XY: 0.413

Gnomad AFR exome AF: 0.0891

Gnomad AMR exome AF: 0.412

Gnomad ASJ exome AF: 0.540

Gnomad EAS exome AF: 0.330

Gnomad FIN exome AF: 0.530

Gnomad NFE exome AF: 0.529

Gnomad OTH exome AF: 0.451

GnomAD4 exome AF: 0.485 AC: 708537 AN: 1461788 Hom.: 182530 Cov.: 59 AF XY: 0.475 AC XY: 345628 AN XY: 727190

African (AFR) AF: 0.0771 AC: 2581 AN: 33474

American (AMR) AF: 0.411 AC: 18372 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.537 AC: 14023 AN: 26134

East Asian (EAS) AF: 0.349 AC: 13851 AN: 39694

South Asian (SAS) AF: 0.129 AC: 11161 AN: 86258

European-Finnish (FIN) AF: 0.541 AC: 28923 AN: 53416

Middle Eastern (MID) AF: 0.296 AC: 1706 AN: 5766

European-Non Finnish (NFE) AF: 0.532 AC: 591007 AN: 1111930

Other (OTH) AF: 0.446 AC: 26913 AN: 60392

GnomAD4 genome AF: 0.381 AC: 57866 AN: 152016 Hom.: 13929 Cov.: 32 AF XY: 0.377 AC XY: 28039 AN XY: 74286

African (AFR) AF: 0.0964 AC: 4002 AN: 41496

American (AMR) AF: 0.435 AC: 6642 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.540 AC: 1875 AN: 3470

East Asian (EAS) AF: 0.341 AC: 1758 AN: 5156

South Asian (SAS) AF: 0.128 AC: 617 AN: 4814

European-Finnish (FIN) AF: 0.535 AC: 5637 AN: 10538

Middle Eastern (MID) AF: 0.330 AC: 97 AN: 294

European-Non Finnish (NFE) AF: 0.529 AC: 35922 AN: 67954

Other (OTH) AF: 0.385 AC: 811 AN: 2108

Alfa AF: 0.477 Hom.: 77191

Bravo AF: 0.365

TwinsUK AF: 0.539 AC: 1997

ALSPAC AF: 0.534 AC: 2058

ESP6500AA AF: 0.110 AC: 483

ESP6500EA AF: 0.525 AC: 4514

ExAC AF: 0.411 AC: 49863

Asia WGS AF: 0.210 AC: 733 AN: 3478

EpiCase AF: 0.536

EpiControl AF: 0.537

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Alpha-methylacyl-CoA racemase deficiency (4)
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Congenital bile acid synthesis defect 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.0040	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.9	H
PhyloP100		4.5
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Uncertain	0.57
Sift	Benign	0.049	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.93	P
Vest4		0.27
MPC		0.24
ClinPred		0.099	T
GERP RS		5.9
Varity_R		0.68
gMVP		0.89
Mutation Taster		=7/93	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs10941112; hg19: chr5-34004707; COSMIC: COSV59461134;