NM_014324.6:c.353G>C

Variant names:

• chr5-34005794-C-G
• rs16892150
• NM_014324.6:c.353G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014324.6(AMACR):​c.353G>C​(p.Arg118Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R118Q) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: AMACR NM_014324.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.50
• 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]

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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12071863).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AMACR	NM_014324.6	c.353G>C	p.Arg118Pro	missense_variant	Exon 2 of 5	ENST00000335606.11	NP_055139.4
AMACR	NM_001167595.2	c.353G>C	p.Arg118Pro	missense_variant	Exon 2 of 6		NP_001161067.1
AMACR	NM_203382.3	c.353G>C	p.Arg118Pro	missense_variant	Exon 2 of 4		NP_976316.1
C1QTNF3-AMACR	NR_037951.1	n.870G>C		non_coding_transcript_exon_variant	Exon 7 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AMACR	ENST00000335606.11	c.353G>C	p.Arg118Pro	missense_variant	Exon 2 of 5	1	NM_014324.6	ENSP00000334424.6
ENSG00000289791	ENST00000426255.6	c.353G>C	p.Arg118Pro	missense_variant	Exon 2 of 5	2		ENSP00000476965.1
C1QTNF3-AMACR	ENST00000382079.3	n.795G>C		non_coding_transcript_exon_variant	Exon 7 of 9	2		ENSP00000371511.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461864 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727232

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	6.0
DANN	Benign	0.90
DEOGEN2	Benign	0.060	T;.;.;.;T;T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.044	N
LIST_S2	Uncertain	0.93	D;D;D;D;D;D;D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.12	T;T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.42	N;N;N;.;.;.;.
PhyloP100		-1.5
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-1.6	N;N;N;N;.;.;.
REVEL	Benign	0.084
Sift	Benign	0.30	T;T;T;T;.;.;.
Sift4G	Benign	0.38	T;T;T;T;T;T;T
Polyphen		0.0	B;B;.;B;.;.;.
Vest4		0.37
MutPred		0.49		Gain of glycosylation at S113 (P = 0.0805);Gain of glycosylation at S113 (P = 0.0805);Gain of glycosylation at S113 (P = 0.0805);Gain of glycosylation at S113 (P = 0.0805);Gain of glycosylation at S113 (P = 0.0805);Gain of glycosylation at S113 (P = 0.0805);Gain of glycosylation at S113 (P = 0.0805);
MVP		0.33
MPC		0.073
ClinPred		0.057	T
GERP RS		-3.5
Varity_R		0.25
gMVP		0.76
Mutation Taster		=82/18	polymorphism

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: rs16892150; hg19: chr5-34005899;