rs3195676

chr5-34007995-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.25G>A(p.Val9Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.482 in 1,610,698 control chromosomes in the GnomAD database, including 198,943 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V9V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.41 (14732 hom., cov: 32)
  • Exomes 𝑓: 0.49 (184211 hom.)
• Consequence: AMACR NM_014324.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.850

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=7.387839E-5).
• BP6: Variant 5-34007995-C-T is Benign according to our data. Variant chr5-34007995-C-T is described in ClinVar as [Benign]. Clinvar id is 128356.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-34007995-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.526 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AMACR	NM_014324.6	c.25G>A	p.Val9Met	missense_variant	1/5	ENST00000335606.11
C1QTNF3-AMACR	NR_037951.1	n.765-2096G>A		intron_variant, non_coding_transcript_variant
AMACR	NM_001167595.2	c.25G>A	p.Val9Met	missense_variant	1/6
AMACR	NM_203382.3	c.25G>A	p.Val9Met	missense_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AMACR	ENST00000335606.11	c.25G>A	p.Val9Met	missense_variant	1/5	1	NM_014324.6	P1

Frequencies

GnomAD3 genomes AF: 0.412 AC: 62593 AN: 151940 Hom.: 14732 Cov.: 32

Gnomad AFR AF: 0.201

Gnomad AMI AF: 0.554

Gnomad AMR AF: 0.447

Gnomad ASJ AF: 0.540

Gnomad EAS AF: 0.344

Gnomad SAS AF: 0.129

Gnomad FIN AF: 0.536

Gnomad MID AF: 0.331

Gnomad NFE AF: 0.531

Gnomad OTH AF: 0.416

GnomAD3 exomes AF: 0.424 AC: 100169 AN: 236178 Hom.: 23930 AF XY: 0.416 AC XY: 53860 AN XY: 129622

Gnomad AFR exome AF: 0.194

Gnomad AMR exome AF: 0.425

Gnomad ASJ exome AF: 0.540

Gnomad EAS exome AF: 0.333

Gnomad SAS exome AF: 0.127

Gnomad FIN exome AF: 0.526

Gnomad NFE exome AF: 0.529

Gnomad OTH exome AF: 0.454

GnomAD4 exome AF: 0.490 AC: 714023 AN: 1458640 Hom.: 184211 Cov.: 72 AF XY: 0.480 AC XY: 348012 AN XY: 725690

Gnomad4 AFR exome AF: 0.185

Gnomad4 AMR exome AF: 0.423

Gnomad4 ASJ exome AF: 0.537

Gnomad4 EAS exome AF: 0.352

Gnomad4 SAS exome AF: 0.131

Gnomad4 FIN exome AF: 0.541

Gnomad4 NFE exome AF: 0.534

Gnomad4 OTH exome AF: 0.454

GnomAD4 genome AF: 0.412 AC: 62597 AN: 152058 Hom.: 14732 Cov.: 32 AF XY: 0.408 AC XY: 30309 AN XY: 74320

Gnomad4 AFR AF: 0.200

Gnomad4 AMR AF: 0.447

Gnomad4 ASJ AF: 0.540

Gnomad4 EAS AF: 0.344

Gnomad4 SAS AF: 0.131

Gnomad4 FIN AF: 0.536

Gnomad4 NFE AF: 0.531

Gnomad4 OTH AF: 0.410

Alfa AF: 0.505 Hom.: 41580

Bravo AF: 0.401

TwinsUK AF: 0.540 AC: 2004

ALSPAC AF: 0.535 AC: 2063

ESP6500AA AF: 0.210 AC: 920

ESP6500EA AF: 0.524 AC: 4492

ExAC AF: 0.417 AC: 50167

Asia WGS AF: 0.221 AC: 772 AN: 3478

EpiCase AF: 0.538

EpiControl AF: 0.537

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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. -
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. -

Alpha-methylacyl-CoA racemase deficiency Benign:3

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	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

Congenital bile acid synthesis defect 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

not provided Benign:1

Benign, no assertion criteria provided

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Oct 22, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	4.1
Dann	Uncertain	0.98
DEOGEN2	Benign	0.25	T;.;.;.;T;T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.065	N
LIST_S2	Benign	0.80	T;T;T;T;T;T;T
MetaRNN	Benign	0.000074	T;T;T;T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Pathogenic	3.0	M;M;M;.;.;.;.
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.46	N;N;N;N;.;.;.
REVEL	Benign	0.23
Sift	Benign	0.038	D;T;D;D;.;.;.
Sift4G	Uncertain	0.0070	D;D;D;D;D;D;D
Polyphen		0.15	B;P;.;B;.;.;.
Vest4		0.11
MPC		0.94
ClinPred		0.043	T
GERP RS		-9.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.16
gMVP		0.29

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

Other links and lift over

dbSNP: rs3195676; hg19: chr5-34008100; COSMIC: COSV59461909;