Genetic Variant AMACR:c.553-826A>G (chr5-33999653-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_014324.6(AMACR):c.553-826A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.736 in 152,200 control chromosomes in the GnomAD database, including 41,582 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.74 ( 41582 hom., cov: 33)

Consequence

AMACR
NM_014324.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.115

Publications

5 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: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.817 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
AMACR	NM_014324.6 link	c.553-826A>G	intron_variant	Intron 3 of 4	ENST00000335606.11	NP_055139.4	Q9UHK6-1
AMACR	NM_001167595.2 link	c.553-826A>G	intron_variant	Intron 3 of 5		NP_001161067.1	Q9UHK6-5
AMACR	NM_203382.3 link	c.392-826A>G	intron_variant	Intron 2 of 3		NP_976316.1	Q9UHK6-4
C1QTNF3-AMACR	NR_037951.1 link	n.909-826A>G	intron_variant	Intron 7 of 8

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
AMACR	ENST00000335606.11 link	c.553-826A>G	intron_variant	Intron 3 of 4	1	NM_014324.6	ENSP00000334424.6	Q9UHK6-1
ENSG00000289791	ENST00000426255.6 link	c.553-826A>G	intron_variant	Intron 3 of 4	2		ENSP00000476965.1	V9GYP4
C1QTNF3-AMACR	ENST00000382079.3 link	n.834-826A>G	intron_variant	Intron 7 of 8	2		ENSP00000371511.3	E9PGA6

Frequencies

GnomAD3 genomes

AF:

0.736

AC:

111860

AN:

152082

Hom.:

41544

Cov.:

show subpopulations

Gnomad AFR

AF:

0.809

Gnomad AMI

AF:

0.678

Gnomad AMR

AF:

0.714

Gnomad ASJ

AF:

0.760

Gnomad EAS

AF:

0.838

Gnomad SAS

AF:

0.497

Gnomad FIN

AF:

0.725

Gnomad MID

AF:

0.639

Gnomad NFE

AF:

0.707

Gnomad OTH

AF:

0.717

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.736

AC:

111947

AN:

152200

Hom.:

41582

Cov.:

AF XY:

0.733

AC XY:

54563

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.809

AC:

33592

AN:

41514

American (AMR)

AF:

0.714

AC:

10919

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.760

AC:

2638

AN:

3472

East Asian (EAS)

AF:

0.837

AC:

4348

AN:

5192

South Asian (SAS)

AF:

0.496

AC:

2395

AN:

4824

European-Finnish (FIN)

AF:

0.725

AC:

7679

AN:

10592

Middle Eastern (MID)

AF:

0.636

AC:

187

AN:

294

European-Non Finnish (NFE)

AF:

0.707

AC:

48068

AN:

68000

Other (OTH)

AF:

0.713

AC:

1504

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1504

3008

4512

6016

7520

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

836

1672

2508

3344

4180

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.723

Hom.:

8316

Bravo

AF:

0.746

Asia WGS

AF:

0.625

AC:

2174

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

1.6

(source)

DANN

Benign

0.68

PhyloP100

0.12

Mutation Taster

=100/0

polymorphism (auto)

(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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over