5-34005794-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.353G>A(p.Arg118Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00558 in 1,614,058 control chromosomes in the GnomAD database, including 429 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R118W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.030 (218 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (211 hom.)
• Consequence: AMACR NM_014324.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.50

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=0.0019286871).
• BP6: Variant 5-34005794-C-T is Benign according to our data. Variant chr5-34005794-C-T is described in ClinVar as [Benign]. Clinvar id is 353255.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.1 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AMACR	NM_014324.6	c.353G>A	p.Arg118Gln	missense_variant	2/5	ENST00000335606.11
C1QTNF3-AMACR	NR_037951.1	n.870G>A		non_coding_transcript_exon_variant	7/9
AMACR	NM_001167595.2	c.353G>A	p.Arg118Gln	missense_variant	2/6
AMACR	NM_203382.3	c.353G>A	p.Arg118Gln	missense_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AMACR	ENST00000335606.11	c.353G>A	p.Arg118Gln	missense_variant	2/5	1	NM_014324.6	P1

Frequencies

GnomAD3 genomes AF: 0.0296 AC: 4494 AN: 152076 Hom.: 217 Cov.: 32

Gnomad AFR AF: 0.103

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0107

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.0259

GnomAD3 exomes AF: 0.00781 AC: 1962 AN: 251340 Hom.: 92 AF XY: 0.00571 AC XY: 776 AN XY: 135866

Gnomad AFR exome AF: 0.109

Gnomad AMR exome AF: 0.00431

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000220

Gnomad OTH exome AF: 0.00391

GnomAD4 exome AF: 0.00309 AC: 4513 AN: 1461864 Hom.: 211 Cov.: 31 AF XY: 0.00266 AC XY: 1937 AN XY: 727232

Gnomad4 AFR exome AF: 0.109

Gnomad4 AMR exome AF: 0.00499

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000185

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000158

Gnomad4 OTH exome AF: 0.00695

GnomAD4 genome AF: 0.0295 AC: 4497 AN: 152194 Hom.: 218 Cov.: 32 AF XY: 0.0279 AC XY: 2076 AN XY: 74420

Gnomad4 AFR AF: 0.103

Gnomad4 AMR AF: 0.0107

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.0256

Alfa AF: 0.00395 Hom.: 54

Bravo AF: 0.0341

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0983 AC: 433

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00953 AC: 1157

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000296

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Alpha-methylacyl-CoA racemase deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 24, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.71
Cadd	Benign	1.3
Dann	Benign	0.85
DEOGEN2	Benign	0.023	T;.;.;.;T;T;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.023	N
LIST_S2	Uncertain	0.87	D;D;D;D;T;T;D
MetaRNN	Benign	0.0019	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.46	N;N;N;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.20	T
PROVEAN	Benign	0.12	N;N;N;N;.;.;.
REVEL	Benign	0.014
Sift	Benign	0.76	T;T;T;T;.;.;.
Sift4G	Benign	0.81	T;T;T;T;T;T;T
Polyphen		0.0020	B;B;.;B;.;.;.
Vest4		0.092
MVP		0.33
MPC		0.060
ClinPred		0.0017	T
GERP RS		-3.5
Varity_R		0.017
gMVP		0.32

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: rs16892150; hg19: chr5-34005899;