Genetic Variant NM_014324.6:c.781A>T (chr5-33989461-T-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_014324.6(AMACR):c.781A>T(p.Met261Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M261I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

AMACR
NM_014324.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -0.122

Publications

0 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:

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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=0.040356934).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AMACR	NM_014324.6	MANE Select	c.781A>T	p.Met261Leu	missense	Exon 5 of 5	NP_055139.4
AMACR	NM_001167595.2		c.781A>T	p.Met261Leu	missense	Exon 5 of 6	NP_001161067.1	Q9UHK6-5
AMACR	NM_203382.3		c.*23A>T		3_prime_UTR	Exon 4 of 4	NP_976316.1	Q9UHK6-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AMACR	ENST00000335606.11	TSL:1 MANE Select	c.781A>T	p.Met261Leu	missense	Exon 5 of 5	ENSP00000334424.6	Q9UHK6-1
AMACR	ENST00000382085.7	TSL:1	c.781A>T	p.Met261Leu	missense	Exon 5 of 6	ENSP00000371517.3	Q9UHK6-5
AMACR	ENST00000382072.6	TSL:1	c.*23A>T		3_prime_UTR	Exon 4 of 4	ENSP00000371504.2	Q9UHK6-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Alpha-methylacyl-CoA racemase deficiency (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.71

CADD

Benign

1.2

(source)

DANN

Benign

0.69

DEOGEN2

Benign

0.039

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.076

LIST_S2

Benign

0.73

M_CAP

Benign

0.0058

MetaRNN

Benign

0.040

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

PhyloP100

-0.12

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.71

REVEL

Benign

0.020

Sift

Benign

0.68

Sift4G

Benign

0.60

Polyphen

0.0030

Vest4

0.10

MutPred

0.26

Loss of disorder (P = 0.0796)

MVP

0.11

MPC

0.052

ClinPred

0.025

GERP RS

0.61

Varity_R

0.031

gMVP

0.36

Mutation Taster

=96/4

polymorphism

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over