5-33988117-C-T

Variant names:

• chr5-33988117-C-T
• rs150664086
• NM_014324.6:c.*976G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_014324.6(AMACR):​c.*976G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00989 in 526,660 control chromosomes in the GnomAD database, including 56 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0085 (10 hom., cov: 33)
  • Exomes 𝑓: 0.010 (46 hom.)
• Consequence: AMACR NM_014324.6 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.00900

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]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BP6: Variant 5-33988117-C-T is Benign according to our data. Variant chr5-33988117-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 353240.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00852 (1297/152302) while in subpopulation SAS AF = 0.0313 (151/4826). AF 95% confidence interval is 0.0272. There are 10 homozygotes in GnomAd4. There are 662 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AMACR	NM_014324.6	c.*976G>A		3_prime_UTR_variant	Exon 5 of 5	ENST00000335606.11	NP_055139.4
AMACR	NM_001167595.2	c.*191G>A		3_prime_UTR_variant	Exon 6 of 6		NP_001161067.1
AMACR	NM_203382.3	c.*1367G>A		3_prime_UTR_variant	Exon 4 of 4		NP_976316.1
C1QTNF3-AMACR	NR_037951.1	n.2481G>A		non_coding_transcript_exon_variant	Exon 9 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AMACR	ENST00000335606.11	c.*976G>A		3_prime_UTR_variant	Exon 5 of 5	1	NM_014324.6	ENSP00000334424.6
C1QTNF3-AMACR	ENST00000382079.3	n.*1551G>A		non_coding_transcript_exon_variant	Exon 9 of 9	2		ENSP00000371511.3
C1QTNF3-AMACR	ENST00000382079.3	n.*1551G>A		3_prime_UTR_variant	Exon 9 of 9	2		ENSP00000371511.3

Frequencies

GnomAD3 genomes AF: 0.00854 AC: 1299 AN: 152184 Hom.: 11 Cov.: 33

Gnomad AFR AF: 0.00251

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0186

Gnomad ASJ AF: 0.0176

Gnomad EAS AF: 0.00212

Gnomad SAS AF: 0.0317

Gnomad FIN AF: 0.000660

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.00919

Gnomad OTH AF: 0.0148

GnomAD4 exome AF: 0.0104 AC: 3911 AN: 374358 Hom.: 46 Cov.: 4 AF XY: 0.0112 AC XY: 2174 AN XY: 194648

African (AFR) AF: 0.00320 AC: 36 AN: 11252

American (AMR) AF: 0.0158 AC: 255 AN: 16090

Ashkenazi Jewish (ASJ) AF: 0.0182 AC: 214 AN: 11734

East Asian (EAS) AF: 0.000704 AC: 20 AN: 28390

South Asian (SAS) AF: 0.0255 AC: 695 AN: 27286

European-Finnish (FIN) AF: 0.00129 AC: 32 AN: 24786

Middle Eastern (MID) AF: 0.0333 AC: 88 AN: 2640

European-Non Finnish (NFE) AF: 0.00997 AC: 2293 AN: 229908

Other (OTH) AF: 0.0125 AC: 278 AN: 22272

GnomAD4 genome AF: 0.00852 AC: 1297 AN: 152302 Hom.: 10 Cov.: 33 AF XY: 0.00889 AC XY: 662 AN XY: 74486

African (AFR) AF: 0.00253 AC: 105 AN: 41566

American (AMR) AF: 0.0186 AC: 284 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0176 AC: 61 AN: 3464

East Asian (EAS) AF: 0.00212 AC: 11 AN: 5186

South Asian (SAS) AF: 0.0313 AC: 151 AN: 4826

European-Finnish (FIN) AF: 0.000660 AC: 7 AN: 10614

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.00916 AC: 623 AN: 68022

Other (OTH) AF: 0.0156 AC: 33 AN: 2116

Alfa AF: 0.00813 Hom.: 2

Bravo AF: 0.00916

Asia WGS AF: 0.0210 AC: 75 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Alpha-methylacyl-CoA racemase deficiency Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	2.3
DANN	Benign	0.50
PhyloP100		0.0090
Mutation Taster		=100/0	polymorphism

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

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Other links and lift over

dbSNP: rs150664086; hg19: chr5-33988222;