rs10941112

Positions:

• chr5-34004602-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 4.50

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]

C1QTNF3-AMACR (HGNC:):

ACMG classification

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	UniProt
AMACR	NM_014324.6	c.524G>A	p.Gly175Asp	missense_variant	3/5	ENST00000335606.11
C1QTNF3-AMACR	NR_037951.1	n.908+1154G>A		intron_variant, non_coding_transcript_variant
AMACR	NM_001167595.2	c.524G>A	p.Gly175Asp	missense_variant	3/6
AMACR	NM_203382.3	c.391+1154G>A		intron_variant

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.381 AC: 57872 AN: 151898 Hom.: 13930 Cov.: 32

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

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.: 59 AF XY: 0.475 AC XY: 345628 AN XY: 727190

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.: 32 AF XY: 0.377 AC XY: 28039 AN XY: 74286

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

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	T
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	26
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	D
LIST_S2	Benign	0.72	T;T;T;T;T
MetaRNN	Benign	0.0040	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.9	H;H;.;.;.
MutationTaster	Benign	6.2e-13	P;P;P;P;P
PrimateAI	Benign	0.48	T
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	T
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

Other links and lift over

dbSNP: rs10941112; hg19: chr5-34004707; COSMIC: COSV59461134;