rs145786819

Variant names:

• chr5-33998826-A-G
• rs145786819
• NM_014324.6:c.554T>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_014324.6(AMACR):​c.554T>C​(p.Val185Ala) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00111 in 1,613,938 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00083 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (3 hom.)
• Consequence: AMACR NM_014324.6 missense, splice_region
• Scores: Splicing: ADA: 0.2734
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:1
• Conservation: PhyloP100: 9.06
• Publications: 7 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3941239).
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

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.554T>C	p.Val185Ala	missense splice_region	Exon 4 of 5	NP_055139.4
	AMACR	NM_001167595.2		c.554T>C	p.Val185Ala	missense splice_region	Exon 4 of 6	NP_001161067.1	Q9UHK6-5
	AMACR	NM_203382.3		c.393T>C	p.Gly131Gly	splice_region synonymous	Exon 3 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.554T>C	p.Val185Ala	missense splice_region	Exon 4 of 5	ENSP00000334424.6	Q9UHK6-1
	AMACR	ENST00000382085.7	TSL:1	c.554T>C	p.Val185Ala	missense splice_region	Exon 4 of 6	ENSP00000371517.3	Q9UHK6-5
	ENSG00000289791	ENST00000426255.6	TSL:2	c.554T>C	p.Val185Ala	missense splice_region	Exon 4 of 5	ENSP00000476965.1	V9GYP4

Frequencies

GnomAD3 genomes AF: 0.000841 AC: 128 AN: 152184 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00116

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000947 AC: 238 AN: 251326 AF XY: 0.00105

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.000723

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000693

Gnomad NFE exome AF: 0.00121

Gnomad OTH exome AF: 0.000979

GnomAD4 exome AF: 0.00114 AC: 1664 AN: 1461636 Hom.: 3 Cov.: 33 AF XY: 0.00118 AC XY: 858 AN XY: 727150

African (AFR) AF: 0.000209 AC: 7 AN: 33472

American (AMR) AF: 0.000984 AC: 44 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00150 AC: 129 AN: 86258

European-Finnish (FIN) AF: 0.000506 AC: 27 AN: 53406

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5766

European-Non Finnish (NFE) AF: 0.00125 AC: 1394 AN: 1111802

Other (OTH) AF: 0.000994 AC: 60 AN: 60392

GnomAD4 genome AF: 0.000827 AC: 126 AN: 152302 Hom.: 1 Cov.: 33 AF XY: 0.000658 AC XY: 49 AN XY: 74466

African (AFR) AF: 0.000457 AC: 19 AN: 41560

American (AMR) AF: 0.00118 AC: 18 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4828

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00116 AC: 79 AN: 68030

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.000859 Hom.: 0

Bravo AF: 0.000945

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000914 AC: 111

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000872

EpiControl AF: 0.00130

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	4	1	not provided (5)
-	2	-	Alpha-methylacyl-CoA racemase deficiency (2)
-	1	-	AMACR-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.037	T
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	2.0	M
PhyloP100		9.1
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.62
Sift	Benign	0.069	T
Sift4G	Uncertain	0.054	T
Polyphen		0.43	B
Vest4		0.82
MVP		0.63
MPC		0.31
ClinPred		0.038	T
GERP RS		5.5
Varity_R		0.55
gMVP		0.73
Mutation Taster		=24/76	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.27
dbscSNV1_RF	Benign	0.40
SpliceAI score (max)		0.020		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: rs145786819; hg19: chr5-33998931;