5-33988023-G-A

Variant names:

• chr5-33988023-G-A
• rs16892064
• NM_014324.6:c.*1070C>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.*1070C>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 0.031 in 248,714 control chromosomes in the GnomAD database, including 387 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.036 (224 hom., cov: 33)
  • Exomes 𝑓: 0.024 (163 hom.)
• Consequence: AMACR NM_014324.6 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.583

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=-0.9).
• BP6: Variant 5-33988023-G-A is Benign according to our data. Variant chr5-33988023-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 353238.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.156 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AMACR	NM_014324.6	c.*1070C>T		3_prime_UTR_variant	Exon 5 of 5	ENST00000335606.11	NP_055139.4
AMACR	NM_001167595.2	c.*285C>T		3_prime_UTR_variant	Exon 6 of 6		NP_001161067.1
AMACR	NM_203382.3	c.*1461C>T		3_prime_UTR_variant	Exon 4 of 4		NP_976316.1
C1QTNF3-AMACR	NR_037951.1	n.2575C>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.*1070C>T		3_prime_UTR_variant	Exon 5 of 5	1	NM_014324.6	ENSP00000334424.6
C1QTNF3-AMACR	ENST00000382079.3	n.*1645C>T		non_coding_transcript_exon_variant	Exon 9 of 9	2		ENSP00000371511.3
C1QTNF3-AMACR	ENST00000382079.3	n.*1645C>T		3_prime_UTR_variant	Exon 9 of 9	2		ENSP00000371511.3

Frequencies

GnomAD3 genomes AF: 0.0355 AC: 5393 AN: 152096 Hom.: 223 Cov.: 33

Gnomad AFR AF: 0.0749

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0446

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.166

Gnomad SAS AF: 0.0523

Gnomad FIN AF: 0.0171

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00357

Gnomad OTH AF: 0.0325

GnomAD4 exome AF: 0.0240 AC: 2314 AN: 96500 Hom.: 163 Cov.: 0 AF XY: 0.0223 AC XY: 1090 AN XY: 48972

African (AFR) AF: 0.0717 AC: 252 AN: 3516

American (AMR) AF: 0.0482 AC: 141 AN: 2924

Ashkenazi Jewish (ASJ) AF: 0.00274 AC: 11 AN: 4014

East Asian (EAS) AF: 0.162 AC: 1364 AN: 8394

South Asian (SAS) AF: 0.0514 AC: 55 AN: 1070

European-Finnish (FIN) AF: 0.0125 AC: 70 AN: 5620

Middle Eastern (MID) AF: 0.0162 AC: 9 AN: 556

European-Non Finnish (NFE) AF: 0.00344 AC: 219 AN: 63682

Other (OTH) AF: 0.0287 AC: 193 AN: 6724

GnomAD4 genome AF: 0.0355 AC: 5408 AN: 152214 Hom.: 224 Cov.: 33 AF XY: 0.0375 AC XY: 2787 AN XY: 74410

African (AFR) AF: 0.0749 AC: 3112 AN: 41526

American (AMR) AF: 0.0449 AC: 686 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3470

East Asian (EAS) AF: 0.165 AC: 852 AN: 5160

South Asian (SAS) AF: 0.0519 AC: 250 AN: 4818

European-Finnish (FIN) AF: 0.0171 AC: 181 AN: 10614

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

European-Non Finnish (NFE) AF: 0.00357 AC: 243 AN: 68022

Other (OTH) AF: 0.0350 AC: 74 AN: 2112

Alfa AF: 0.0279 Hom.: 120

Bravo AF: 0.0397

Asia WGS AF: 0.109 AC: 376 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

- -

Mar 24, 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	-0.90
CADD	Benign	4.5
DANN	Benign	0.72
PhyloP100		0.58
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: rs16892064; hg19: chr5-33988128;