rs3195678

Positions:

• chr5-33989460-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_014324.6(AMACR):​c.782T>C​(p.Met261Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00218 in 1,614,186 control chromosomes in the GnomAD database, including 87 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (47 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (40 hom.)
• Consequence: AMACR NM_014324.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.25

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=0.002657652).
• BP6: Variant 5-33989460-A-G is Benign according to our data. Variant chr5-33989460-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 235412.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0119 (1820/152316) while in subpopulation AFR AF= 0.0422 (1752/41556). AF 95% confidence interval is 0.0405. There are 47 homozygotes in gnomad4. There are 856 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 47 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AMACR	NM_014324.6	c.782T>C	p.Met261Thr	missense_variant	5/5	ENST00000335606.11	NP_055139.4
C1QTNF3-AMACR	NR_037951.1	n.1138T>C		non_coding_transcript_exon_variant	9/9
AMACR	NM_001167595.2	c.782T>C	p.Met261Thr	missense_variant	5/6		NP_001161067.1
AMACR	NM_203382.3	c.*24T>C		3_prime_UTR_variant	4/4		NP_976316.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AMACR	ENST00000335606.11	c.782T>C	p.Met261Thr	missense_variant	5/5	1	NM_014324.6	ENSP00000334424	P1

Frequencies

GnomAD3 genomes AF: 0.0119 AC: 1805 AN: 152198 Hom.: 46 Cov.: 33

Gnomad AFR AF: 0.0419

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00716

GnomAD3 exomes AF: 0.00287 AC: 721 AN: 251300 Hom.: 23 AF XY: 0.00206 AC XY: 280 AN XY: 135830

Gnomad AFR exome AF: 0.0393

Gnomad AMR exome AF: 0.00191

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.00116 AC: 1703 AN: 1461870 Hom.: 40 Cov.: 34 AF XY: 0.00102 AC XY: 741 AN XY: 727236

Gnomad4 AFR exome AF: 0.0424

Gnomad4 AMR exome AF: 0.00197

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000279

Gnomad4 OTH exome AF: 0.00227

GnomAD4 genome AF: 0.0119 AC: 1820 AN: 152316 Hom.: 47 Cov.: 33 AF XY: 0.0115 AC XY: 856 AN XY: 74490

Gnomad4 AFR AF: 0.0422

Gnomad4 AMR AF: 0.00288

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00709

Alfa AF: 0.00217 Hom.: 10

Bravo AF: 0.0135

ESP6500AA AF: 0.0372 AC: 164

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00372 AC: 452

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 19, 2016	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 17, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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	Labcorp Genetics (formerly Invitae), Labcorp	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. -

Congenital bile acid synthesis defect 4;C3280428:Alpha-methylacyl-CoA racemase deficiency Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 08, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.82
DANN	Benign	0.53
DEOGEN2	Benign	0.052	T;.;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.41	T;T;T
MetaRNN	Benign	0.0027	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L;L;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.7	N;N;N
REVEL	Benign	0.050
Sift	Benign	0.75	T;T;T
Sift4G	Benign	0.70	T;T;T
Polyphen		0.0090	B;.;B
Vest4		0.012
MVP		0.20
MPC		0.061
ClinPred		0.0062	T
GERP RS		-5.4
Varity_R		0.025
gMVP		0.43

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: rs3195678; hg19: chr5-33989565; COSMIC: COSV99031127; COSMIC: COSV99031127;