5-33998778-A-G

Variant names:

• chr5-33998778-A-G
• rs2287939
• NM_014324.6:c.602T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014324.6(AMACR):​c.602T>C​(p.Leu201Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.708 in 1,613,612 control chromosomes in the GnomAD database, including 408,251 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L201W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.74 (41522 hom., cov: 31)
  • Exomes 𝑓: 0.71 (366729 hom.)
• Consequence: AMACR NM_014324.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.718
• Publications: 51 publications found

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]

ENSG00000289791 (HGNC:):

C1QTNF3-AMACR (HGNC:49198): (C1QTNF3-AMACR readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring C1q and tumor necrosis factor related protein 3 (C1QTNF3) and alpha-methylacyl-CoA racemase (AMACR) genes on chromosome 5. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is thus not likely to produce a protein product. [provided by RefSeq, Mar 2011]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.1085564E-6).
• BP6: Variant 5-33998778-A-G is Benign according to our data. Variant chr5-33998778-A-G is described in ClinVar as Benign. ClinVar VariationId is 128358.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.817 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014324.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AMACR	NM_014324.6	MANE Select	c.602T>C	p.Leu201Ser	missense	Exon 4 of 5	NP_055139.4
	AMACR	NM_001167595.2		c.602T>C	p.Leu201Ser	missense	Exon 4 of 6	NP_001161067.1	Q9UHK6-5
	AMACR	NM_203382.3		c.441T>C	p.Ile147Ile	synonymous	Exon 3 of 4	NP_976316.1	Q9UHK6-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AMACR	ENST00000335606.11	TSL:1 MANE Select	c.602T>C	p.Leu201Ser	missense	Exon 4 of 5	ENSP00000334424.6	Q9UHK6-1
	AMACR	ENST00000382085.7	TSL:1	c.602T>C	p.Leu201Ser	missense	Exon 4 of 6	ENSP00000371517.3	Q9UHK6-5
	ENSG00000289791	ENST00000426255.6	TSL:2	c.602T>C	p.Leu201Ser	missense	Exon 4 of 5	ENSP00000476965.1	V9GYP4

Frequencies

GnomAD3 genomes AF: 0.736 AC: 111701 AN: 151842 Hom.: 41481 Cov.: 31

Gnomad AFR AF: 0.811

Gnomad AMI AF: 0.676

Gnomad AMR AF: 0.715

Gnomad ASJ AF: 0.760

Gnomad EAS AF: 0.838

Gnomad SAS AF: 0.497

Gnomad FIN AF: 0.723

Gnomad MID AF: 0.639

Gnomad NFE AF: 0.706

Gnomad OTH AF: 0.719

GnomAD2 exomes AF: 0.703 AC: 176769 AN: 251432 AF XY: 0.688

Gnomad AFR exome AF: 0.819

Gnomad AMR exome AF: 0.736

Gnomad ASJ exome AF: 0.752

Gnomad EAS exome AF: 0.826

Gnomad FIN exome AF: 0.728

Gnomad NFE exome AF: 0.705

Gnomad OTH exome AF: 0.706

GnomAD4 exome AF: 0.706 AC: 1031224 AN: 1461650 Hom.: 366729 Cov.: 53 AF XY: 0.699 AC XY: 508070 AN XY: 727152

African (AFR) AF: 0.811 AC: 27158 AN: 33476

American (AMR) AF: 0.729 AC: 32613 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.754 AC: 19696 AN: 26132

East Asian (EAS) AF: 0.856 AC: 33989 AN: 39696

South Asian (SAS) AF: 0.501 AC: 43178 AN: 86254

European-Finnish (FIN) AF: 0.734 AC: 39186 AN: 53414

Middle Eastern (MID) AF: 0.639 AC: 3688 AN: 5768

European-Non Finnish (NFE) AF: 0.710 AC: 789209 AN: 1111818

Other (OTH) AF: 0.704 AC: 42507 AN: 60374

GnomAD4 genome AF: 0.736 AC: 111792 AN: 151962 Hom.: 41522 Cov.: 31 AF XY: 0.733 AC XY: 54448 AN XY: 74262

African (AFR) AF: 0.811 AC: 33616 AN: 41428

American (AMR) AF: 0.715 AC: 10904 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.760 AC: 2637 AN: 3470

East Asian (EAS) AF: 0.838 AC: 4334 AN: 5174

South Asian (SAS) AF: 0.497 AC: 2394 AN: 4818

European-Finnish (FIN) AF: 0.723 AC: 7643 AN: 10564

Middle Eastern (MID) AF: 0.636 AC: 187 AN: 294

European-Non Finnish (NFE) AF: 0.706 AC: 47958 AN: 67948

Other (OTH) AF: 0.714 AC: 1505 AN: 2108

Alfa AF: 0.715 Hom.: 179518

Bravo AF: 0.746

TwinsUK AF: 0.712 AC: 2640

ALSPAC AF: 0.712 AC: 2743

ESP6500AA AF: 0.817 AC: 3598

ESP6500EA AF: 0.714 AC: 6139

ExAC AF: 0.699 AC: 84904

Asia WGS AF: 0.623 AC: 2167 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Alpha-methylacyl-CoA racemase deficiency (3)
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Congenital bile acid synthesis defect 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.0040
DANN	Benign	0.37
DEOGEN2	Benign	0.098	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.058	T
MetaRNN	Benign	0.0000011	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.47	N
PhyloP100		-0.72
PrimateAI	Benign	0.23	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.077
Sift	Benign	0.44	T
Sift4G	Benign	0.69	T
Polyphen		0.0010	B
Vest4		0.11
MPC		0.072
ClinPred		0.0099	T
GERP RS		-6.1
Varity_R		0.050
gMVP		0.70
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2287939; hg19: chr5-33998883; COSMIC: COSV59461114; COSMIC: COSV59461114;