rs2278008

Positions:

• chr5-33989413-C-G
• chr5-33989413-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014324.6(AMACR):​c.829G>C​(p.Glu277Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E277K) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: AMACR NM_014324.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.06

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: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]

AMACR (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.085235655).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AMACR	NM_014324.6	c.829G>C	p.Glu277Gln	missense_variant	5/5	ENST00000335606.11	NP_055139.4
AMACR	NM_001167595.2	c.829G>C	p.Glu277Gln	missense_variant	5/6		NP_001161067.1
AMACR	NM_203382.3	c.*71G>C		3_prime_UTR_variant	4/4		NP_976316.1
C1QTNF3-AMACR	NR_037951.1	n.1185G>C		non_coding_transcript_exon_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AMACR	ENST00000335606.11	c.829G>C	p.Glu277Gln	missense_variant	5/5	1	NM_014324.6	ENSP00000334424.6
C1QTNF3-AMACR	ENST00000382079.3	n.*255G>C		non_coding_transcript_exon_variant	9/9	2		ENSP00000371511.3
C1QTNF3-AMACR	ENST00000382079.3	n.*255G>C		3_prime_UTR_variant	9/9	2		ENSP00000371511.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 64

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	15
DANN	Benign	0.93
DEOGEN2	Benign	0.024	T;.;.
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.67	T;T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.085	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.12	N;N;.
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.20	N;N;N
REVEL	Benign	0.049
Sift	Benign	0.56	T;T;T
Sift4G	Benign	0.38	T;T;T
Polyphen		0.0	B;.;B
Vest4		0.020
MutPred		0.34		Loss of stability (P = 0.0843);Loss of stability (P = 0.0843);.;
MVP		0.48
MPC		0.055
ClinPred		0.46	T
GERP RS		5.7
Varity_R		0.051
gMVP		0.41

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: rs2278008; hg19: chr5-33989518;