Genetic Variant NM_014324.6:c.*2789G>C (chr5-33986304-C-G) – 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.*2789G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.518 in 152,110 control chromosomes in the GnomAD database, including 21,944 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 0.52 ( 21943 hom., cov: 33)

Exomes 𝑓: 0.50 ( 1 hom. )

Consequence

AMACR
NM_014324.6 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0710

Publications

18 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 Gene-Disease associations (from GenCC):

alpha-methylacyl-CoA racemase deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
congenital bile acid synthesis defect 4
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

AMACR links:

Genome browser will be placed here

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=-0.85).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.649 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AMACR	NM_014324.6	MANE Select	c.*2789G>C		3_prime_UTR	Exon 5 of 5	NP_055139.4
	AMACR	NM_203382.3		c.*3180G>C		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	ENST00000335606.11	TSL:1 MANE Select	c.*2789G>C		3_prime_UTR	Exon 5 of 5	ENSP00000334424.6	Q9UHK6-1

Frequencies

GnomAD3 genomes

AF:

0.519

AC:

78813

AN:

151982

Hom.:

21939

Cov.:

show subpopulations

Gnomad AFR

AF:

0.323

Gnomad AMI

AF:

0.590

Gnomad AMR

AF:

0.521

Gnomad ASJ

AF:

0.582

Gnomad EAS

AF:

0.667

Gnomad SAS

AF:

0.286

Gnomad FIN

AF:

0.652

Gnomad MID

AF:

0.358

Gnomad NFE

AF:

0.619

Gnomad OTH

AF:

0.510

GnomAD4 exome

AF:

0.500

AC:

AN:

Hom.:

Cov.:

AF XY:

0.500

AC XY:

AN XY:

show subpopulations

African (AFR)

AF:

0.250

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.750

AC:

AN:

Other (OTH)

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.600

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.518

AC:

78832

AN:

152102

Hom.:

21943

Cov.:

AF XY:

0.516

AC XY:

38335

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.322

AC:

13367

AN:

41482

American (AMR)

AF:

0.521

AC:

7970

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.582

AC:

2019

AN:

3472

East Asian (EAS)

AF:

0.667

AC:

3452

AN:

5174

South Asian (SAS)

AF:

0.286

AC:

1380

AN:

4826

European-Finnish (FIN)

AF:

0.652

AC:

6878

AN:

10552

Middle Eastern (MID)

AF:

0.344

AC:

101

AN:

294

European-Non Finnish (NFE)

AF:

0.619

AC:

42051

AN:

67984

Other (OTH)

AF:

0.509

AC:

1077

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1826

3652

5478

7304

9130

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

674

1348

2022

2696

3370

<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:

0.435

Hom.:

1312

Bravo

AF:

0.509

Asia WGS

AF:

0.435

AC:

1513

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.92

(source)

DANN

Benign

0.55

PhyloP100

0.071

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over