5-34005827-A-C

Variant names:

• chr5-34005827-A-C
• rs121917816
• NM_014324.6:c.320T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_014324.6(AMACR):​c.320T>G​(p.Leu107Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. L107P) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: AMACR NM_014324.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.93
• Publications: 0 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-34005827-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 5524.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AMACR	NM_014324.6	c.320T>G	p.Leu107Arg	missense_variant	Exon 2 of 5	ENST00000335606.11	NP_055139.4
AMACR	NM_001167595.2	c.320T>G	p.Leu107Arg	missense_variant	Exon 2 of 6		NP_001161067.1
AMACR	NM_203382.3	c.320T>G	p.Leu107Arg	missense_variant	Exon 2 of 4		NP_976316.1
C1QTNF3-AMACR	NR_037951.1	n.837T>G		non_coding_transcript_exon_variant	Exon 7 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AMACR	ENST00000335606.11	c.320T>G	p.Leu107Arg	missense_variant	Exon 2 of 5	1	NM_014324.6	ENSP00000334424.6
ENSG00000289791	ENST00000426255.6	c.320T>G	p.Leu107Arg	missense_variant	Exon 2 of 5	2		ENSP00000476965.1
C1QTNF3-AMACR	ENST00000382079.3	n.762T>G		non_coding_transcript_exon_variant	Exon 7 of 9	2		ENSP00000371511.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461882 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727242

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T;.;.;.;T;T;T
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D
M_CAP	Uncertain	0.089	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.094	D
MutationAssessor	Pathogenic	4.0	H;H;H;.;.;.;.
PhyloP100		6.9
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-5.6	D;D;D;D;.;.;.
REVEL	Pathogenic	0.72
Sift	Pathogenic	0.0	D;D;D;D;.;.;.
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D
Polyphen		1.0	D;D;.;D;.;.;.
Vest4		0.94
MutPred		0.92		Gain of disorder (P = 0.0307);Gain of disorder (P = 0.0307);Gain of disorder (P = 0.0307);Gain of disorder (P = 0.0307);Gain of disorder (P = 0.0307);Gain of disorder (P = 0.0307);Gain of disorder (P = 0.0307);
MVP		0.82
MPC		0.42
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.99
gMVP		0.96
Mutation Taster		=33/67	disease causing

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

Other links and lift over

dbSNP: rs121917816; hg19: chr5-34005932;