5-33989413-C-T

Position:

chr5-33989413-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_014324.6(AMACR):c.829G>A(p.Glu277Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.73 in 1,613,936 control chromosomes in the GnomAD database, including 435,111 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.74 ( 42165 hom., cov: 33)

Exomes 𝑓: 0.73 ( 392946 hom. )

Consequence

AMACR
NM_014324.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 2.06

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:

AMACR (HGNC:):

AMACR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=9.787361E-7).

BP6

Variant 5-33989413-C-T is Benign according to our data. Variant chr5-33989413-C-T is described in ClinVar as [Benign]. Clinvar id is 128360.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-33989413-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.837 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AMACR	NM_014324.6 linkuse as main transcript	c.829G>A	p.Glu277Lys	missense_variant	5/5	ENST00000335606.11	NP_055139.4	Q9UHK6-1
AMACR	NM_001167595.2 linkuse as main transcript	c.829G>A	p.Glu277Lys	missense_variant	5/6		NP_001161067.1	Q9UHK6-5
AMACR	NM_203382.3 linkuse as main transcript	c.*71G>A		3_prime_UTR_variant	4/4		NP_976316.1	Q9UHK6-4
C1QTNF3-AMACR	NR_037951.1 linkuse as main transcript	n.1185G>A		non_coding_transcript_exon_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
AMACR	ENST00000335606.11 linkuse as main transcript	c.829G>A	p.Glu277Lys	missense_variant	5/5	1	NM_014324.6	ENSP00000334424.6	Q9UHK6-1
C1QTNF3-AMACR	ENST00000382079.3 linkuse as main transcript	n.*255G>A		non_coding_transcript_exon_variant	9/9	2		ENSP00000371511.3	E9PGA6
C1QTNF3-AMACR	ENST00000382079.3 linkuse as main transcript	n.*255G>A		3_prime_UTR_variant	9/9	2		ENSP00000371511.3	E9PGA6

Frequencies

GnomAD3 genomes

AF:

0.740

AC:

112547

AN:

152060

Hom.:

42143

Cov.:

show subpopulations

Gnomad AFR

AF:

0.783

Gnomad AMI

AF:

0.765

Gnomad AMR

AF:

0.669

Gnomad ASJ

AF:

0.749

Gnomad EAS

AF:

0.859

Gnomad SAS

AF:

0.431

Gnomad FIN

AF:

0.745

Gnomad MID

AF:

0.601

Gnomad NFE

AF:

0.743

Gnomad OTH

AF:

0.711

GnomAD3 exomes

AF:

0.701

AC:

176238

AN:

251380

Hom.:

63647

AF XY:

0.688

AC XY:

93421

AN XY:

135868

show subpopulations

Gnomad AFR exome

AF:

0.785

Gnomad AMR exome

AF:

0.645

Gnomad ASJ exome

AF:

0.740

Gnomad EAS exome

AF:

0.852

Gnomad SAS exome

AF:

0.422

Gnomad FIN exome

AF:

0.758

Gnomad NFE exome

AF:

0.742

Gnomad OTH exome

AF:

0.712

GnomAD4 exome

AF:

0.729

AC:

1064898

AN:

1461758

Hom.:

392946

Cov.:

AF XY:

0.719

AC XY:

523124

AN XY:

727176

show subpopulations

Gnomad4 AFR exome

AF:

0.779

Gnomad4 AMR exome

AF:

0.646

Gnomad4 ASJ exome

AF:

0.746

Gnomad4 EAS exome

AF:

0.849

Gnomad4 SAS exome

AF:

0.436

Gnomad4 FIN exome

AF:

0.759

Gnomad4 NFE exome

AF:

0.748

Gnomad4 OTH exome

AF:

0.723

GnomAD4 genome

AF:

0.740

AC:

112614

AN:

152178

Hom.:

42165

Cov.:

AF XY:

0.734

AC XY:

54642

AN XY:

74400

show subpopulations

Gnomad4 AFR

AF:

0.783

Gnomad4 AMR

AF:

0.669

Gnomad4 ASJ

AF:

0.749

Gnomad4 EAS

AF:

0.858

Gnomad4 SAS

AF:

0.431

Gnomad4 FIN

AF:

0.745

Gnomad4 NFE

AF:

0.743

Gnomad4 OTH

AF:

0.707

Alfa

AF:

0.744

Hom.:

64724

Bravo

AF:

0.746

TwinsUK

AF:

0.752

AC:

2788

ALSPAC

AF:

0.749

AC:

2885

ESP6500AA

AF:

0.784

AC:

3453

ESP6500EA

AF:

0.747

AC:

6420

ExAC

AF:

0.701

AC:

85161

Asia WGS

AF:

0.595

AC:

2072

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Alpha-methylacyl-CoA racemase deficiency

Benign:4

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not specified

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 05, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 22, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Oculocutaneous albinism

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Congenital bile acid synthesis defect 4

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.68

CADD

Benign

DANN

Benign

0.89

DEOGEN2

Benign

0.041

T;.;.

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.37

FATHMM_MKL

Benign

0.41

LIST_S2

Benign

0.35

T;T;T

MetaRNN

Benign

9.8e-7

T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-0.57

N;N;.

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.36

N;N;N

REVEL

Benign

0.085

Sift

Benign

1.0

T;T;T

Sift4G

Benign

0.46

T;T;T

Polyphen

0.0

B;.;B

Vest4

0.042

MPC

0.059

ClinPred

0.011

GERP RS

5.7

Varity_R

0.046

gMVP

0.39

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over