chr5-34005794-C-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_014324.6(AMACR):c.353G>T(p.Arg118Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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: 6.8e-7 ( 0 hom. )

Consequence

AMACR
NM_014324.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.50

Publications

11 publications found

Variant links:

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]

AMACR links:

ENSG00000289791 (HGNC:):

ENSG00000289791 links:

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]

C1QTNF3-AMACR links:

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ACMG classification

Classification was made for transcript

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=0.12272245).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AMACR	NM_014324.6 link	c.353G>T	p.Arg118Leu	missense_variant	Exon 2 of 5	ENST00000335606.11	NP_055139.4	Q9UHK6-1
AMACR	NM_001167595.2 link	c.353G>T	p.Arg118Leu	missense_variant	Exon 2 of 6		NP_001161067.1	Q9UHK6-5
AMACR	NM_203382.3 link	c.353G>T	p.Arg118Leu	missense_variant	Exon 2 of 4		NP_976316.1	Q9UHK6-4
C1QTNF3-AMACR	NR_037951.1 link	n.870G>T		non_coding_transcript_exon_variant	Exon 7 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
AMACR	ENST00000335606.11 link	c.353G>T	p.Arg118Leu	missense_variant	Exon 2 of 5	1	NM_014324.6	ENSP00000334424.6	Q9UHK6-1
ENSG00000289791	ENST00000426255.6 link	c.353G>T	p.Arg118Leu	missense_variant	Exon 2 of 5	2		ENSP00000476965.1	V9GYP4
C1QTNF3-AMACR	ENST00000382079.3 link	n.795G>T		non_coding_transcript_exon_variant	Exon 7 of 9	2		ENSP00000371511.3	E9PGA6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251340

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461864

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727232

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112012

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.56

CADD

Benign

1.1

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.18

T;.;.;.;T;T;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.057

LIST_S2

Uncertain

0.94

D;D;D;D;D;D;D

M_CAP

Benign

0.027

MetaRNN

Benign

0.12

T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.23

N;N;N;.;.;.;.

PhyloP100

-1.5

PrimateAI

Benign

0.21

PROVEAN

Uncertain

-2.5

D;D;D;N;.;.;.

REVEL

Benign

0.048

Sift

Benign

0.28

T;T;T;T;.;.;.

Sift4G

Benign

0.30

T;T;T;T;T;T;T

Polyphen

0.0030

B;B;.;B;.;.;.

Vest4

0.30

MutPred

0.51

Gain of glycosylation at S113 (P = 0.0968);Gain of glycosylation at S113 (P = 0.0968);Gain of glycosylation at S113 (P = 0.0968);Gain of glycosylation at S113 (P = 0.0968);Gain of glycosylation at S113 (P = 0.0968);Gain of glycosylation at S113 (P = 0.0968);Gain of glycosylation at S113 (P = 0.0968);

MVP

0.33

MPC

0.064

ClinPred

0.10

GERP RS

-3.5

Varity_R

0.088

gMVP

0.49

Mutation Taster

=89/11

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over