5-33988130-G-A

Variant names:

• chr5-33988130-G-A
• rs6898962
• NM_014324.6:c.*963C>T

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.*963C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0157 in 560,132 control chromosomes in the GnomAD database, including 625 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.043 (472 hom., cov: 32)
  • Exomes 𝑓: 0.0055 (153 hom.)
• Consequence: AMACR NM_014324.6 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.928

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=-0.97).
• BP6: Variant 5-33988130-G-A is Benign according to our data. Variant chr5-33988130-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 353241.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.147 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AMACR	NM_014324.6	c.*963C>T		3_prime_UTR_variant	Exon 5 of 5	ENST00000335606.11	NP_055139.4
AMACR	NM_001167595.2	c.*178C>T		3_prime_UTR_variant	Exon 6 of 6		NP_001161067.1
AMACR	NM_203382.3	c.*1354C>T		3_prime_UTR_variant	Exon 4 of 4		NP_976316.1
C1QTNF3-AMACR	NR_037951.1	n.2468C>T		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.*963C>T		3_prime_UTR_variant	Exon 5 of 5	1	NM_014324.6	ENSP00000334424.6
C1QTNF3-AMACR	ENST00000382079.3	n.*1538C>T		non_coding_transcript_exon_variant	Exon 9 of 9	2		ENSP00000371511.3
C1QTNF3-AMACR	ENST00000382079.3	n.*1538C>T		3_prime_UTR_variant	Exon 9 of 9	2		ENSP00000371511.3

Frequencies

GnomAD3 genomes AF: 0.0430 AC: 6547 AN: 152156 Hom.: 473 Cov.: 32

Gnomad AFR AF: 0.150

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.0349

GnomAD4 exome AF: 0.00547 AC: 2231 AN: 407858 Hom.: 153 Cov.: 5 AF XY: 0.00461 AC XY: 982 AN XY: 212884

African (AFR) AF: 0.145 AC: 1717 AN: 11802

American (AMR) AF: 0.00874 AC: 150 AN: 17158

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12448

East Asian (EAS) AF: 0.00 AC: 0 AN: 29474

South Asian (SAS) AF: 0.000280 AC: 9 AN: 32130

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26542

Middle Eastern (MID) AF: 0.0100 AC: 31 AN: 3090

European-Non Finnish (NFE) AF: 0.000243 AC: 61 AN: 251266

Other (OTH) AF: 0.0110 AC: 263 AN: 23948

GnomAD4 genome AF: 0.0431 AC: 6565 AN: 152274 Hom.: 472 Cov.: 32 AF XY: 0.0408 AC XY: 3041 AN XY: 74462

African (AFR) AF: 0.150 AC: 6243 AN: 41544

American (AMR) AF: 0.0143 AC: 219 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 68014

Other (OTH) AF: 0.0345 AC: 73 AN: 2114

Alfa AF: 0.0187 Hom.: 214

Bravo AF: 0.0485

Asia WGS AF: 0.00722 AC: 27 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 20, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oculocutaneous albinism Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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	-0.97
CADD	Benign	0.26
DANN	Benign	0.40
PhyloP100		-0.93
Mutation Taster		=100/0	polymorphism (auto)

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: rs6898962; hg19: chr5-33988235;