ENST00000382085.7:c.1174A>G

Variant names:

• chr5-33988319-T-C
• rs1287477656
• ENST00000382085.7:c.1174A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000382085.7(AMACR):​c.1174A>G​(p.Ile392Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000195 in 1,540,986 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: AMACR ENST00000382085.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0350
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06162402).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000382085.7. 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.*774A>G		3_prime_UTR	Exon 5 of 5	NP_055139.4
	AMACR	NM_001167595.2		c.1174A>G	p.Ile392Val	missense	Exon 6 of 6	NP_001161067.1	Q9UHK6-5
	AMACR	NM_203382.3		c.*1165A>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	ENST00000382085.7	TSL:1	c.1174A>G	p.Ile392Val	missense	Exon 6 of 6	ENSP00000371517.3	Q9UHK6-5
	AMACR	ENST00000335606.11	TSL:1 MANE Select	c.*774A>G		3_prime_UTR	Exon 5 of 5	ENSP00000334424.6	Q9UHK6-1
	AMACR	ENST00000382072.6	TSL:1	c.*1165A>G		3_prime_UTR	Exon 4 of 4	ENSP00000371504.2	Q9UHK6-4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000144 AC: 2 AN: 1388678 Hom.: 0 Cov.: 29 AF XY: 0.00000146 AC XY: 1 AN XY: 685568

African (AFR) AF: 0.0000628 AC: 2 AN: 31828

American (AMR) AF: 0.00 AC: 0 AN: 36062

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25194

East Asian (EAS) AF: 0.00 AC: 0 AN: 36324

South Asian (SAS) AF: 0.00 AC: 0 AN: 79436

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35332

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5706

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1080694

Other (OTH) AF: 0.00 AC: 0 AN: 58102

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152308 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74476

African (AFR) AF: 0.0000241 AC: 1 AN: 41566

American (AMR) AF: 0.00 AC: 0 AN: 15306

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2116

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	2.7
DANN	Benign	0.57
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0060	N
LIST_S2	Benign	0.25	T
M_CAP	Benign	0.0016	T
MetaRNN	Benign	0.062	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.035
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.020	N
REVEL	Benign	0.047
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.62	T
Vest4		0.16
MutPred		0.17		Gain of ubiquitination at K394 (P = 0.0797)
MVP		0.29
MPC		0.048
ClinPred		0.34	T
GERP RS		-0.96
gMVP		0.11
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs1287477656; hg19: chr5-33988424;