chr5-34004602-C-T

Position:

chr5-34004602-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.524G>A(p.Gly175Asp) variant causes a missense change. The variant allele was found at a frequency of 0.475 in 1,613,804 control chromosomes in the GnomAD database, including 196,459 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.38 ( 13929 hom., cov: 32)

Exomes 𝑓: 0.48 ( 182530 hom. )

Consequence

AMACR
NM_014324.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.50

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:):

C1QTNF3-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=0.0040152073).

BP6

Variant 5-34004602-C-T is Benign according to our data. Variant chr5-34004602-C-T is described in ClinVar as [Benign]. Clinvar id is 128357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-34004602-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.524 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
AMACR	NM_014324.6 linkuse as main transcript	c.524G>A	p.Gly175Asp	missense_variant	3/5	ENST00000335606.11
C1QTNF3-AMACR	NR_037951.1 linkuse as main transcript	n.908+1154G>A		intron_variant, non_coding_transcript_variant
AMACR	NM_001167595.2 linkuse as main transcript	c.524G>A	p.Gly175Asp	missense_variant	3/6
AMACR	NM_203382.3 linkuse as main transcript	c.391+1154G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AMACR	ENST00000335606.11 linkuse as main transcript	c.524G>A	p.Gly175Asp	missense_variant	3/5	1	NM_014324.6	P1	Q9UHK6-1

Frequencies

GnomAD3 genomes

AF:

0.381

AC:

57872

AN:

151898

Hom.:

13930

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0967

Gnomad AMI

AF:

0.556

Gnomad AMR

AF:

0.435

Gnomad ASJ

AF:

0.540

Gnomad EAS

AF:

0.341

Gnomad SAS

AF:

0.127

Gnomad FIN

AF:

0.535

Gnomad MID

AF:

0.342

Gnomad NFE

AF:

0.529

Gnomad OTH

AF:

0.389

GnomAD3 exomes

AF:

0.420

AC:

105515

AN:

251448

Hom.:

25527

AF XY:

0.413

AC XY:

56155

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.0891

Gnomad AMR exome

AF:

0.412

Gnomad ASJ exome

AF:

0.540

Gnomad EAS exome

AF:

0.330

Gnomad SAS exome

AF:

0.126

Gnomad FIN exome

AF:

0.530

Gnomad NFE exome

AF:

0.529

Gnomad OTH exome

AF:

0.451

GnomAD4 exome

AF:

0.485

AC:

708537

AN:

1461788

Hom.:

182530

Cov.:

AF XY:

0.475

AC XY:

345628

AN XY:

727190

show subpopulations

Gnomad4 AFR exome

AF:

0.0771

Gnomad4 AMR exome

AF:

0.411

Gnomad4 ASJ exome

AF:

0.537

Gnomad4 EAS exome

AF:

0.349

Gnomad4 SAS exome

AF:

0.129

Gnomad4 FIN exome

AF:

0.541

Gnomad4 NFE exome

AF:

0.532

Gnomad4 OTH exome

AF:

0.446

GnomAD4 genome

AF:

0.381

AC:

57866

AN:

152016

Hom.:

13929

Cov.:

AF XY:

0.377

AC XY:

28039

AN XY:

74286

show subpopulations

Gnomad4 AFR

AF:

0.0964

Gnomad4 AMR

AF:

0.435

Gnomad4 ASJ

AF:

0.540

Gnomad4 EAS

AF:

0.341

Gnomad4 SAS

AF:

0.128

Gnomad4 FIN

AF:

0.535

Gnomad4 NFE

AF:

0.529

Gnomad4 OTH

AF:

0.385

Alfa

AF:

0.493

Hom.:

40438

Bravo

AF:

0.365

TwinsUK

AF:

0.539

AC:

1997

ALSPAC

AF:

0.534

AC:

2058

ESP6500AA

AF:

0.110

AC:

483

ESP6500EA

AF:

0.525

AC:

4514

ExAC

AF:

0.411

AC:

49863

Asia WGS

AF:

0.210

AC:

733

AN:

3478

EpiCase

AF:

0.536

EpiControl

AF:

0.537

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	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
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	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 06, 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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 18, 2017	- -
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. -

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	-	- -

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

0.33

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.12

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.48

T;.;.;T;T

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.72

T;T;T;T;T

MetaRNN

Benign

0.0040

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Pathogenic

3.9

H;H;.;.;.

MutationTaster

Benign

6.2e-13

P;P;P;P;P

PrimateAI

Benign

0.48

PROVEAN

Pathogenic

-4.8

D;D;D;.;.

REVEL

Uncertain

0.57

Sift

Benign

0.049

D;D;D;.;.

Sift4G

Uncertain

0.0060

D;D;D;D;D

Polyphen

0.93

P;.;P;.;.

Vest4

0.27

MPC

0.24

ClinPred

0.099

GERP RS

5.9

Varity_R

0.68

gMVP

0.89

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

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