rs34688

Positions:

• chr5-34007554-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014324.6(AMACR):​c.247+219C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.255 in 152,114 control chromosomes in the GnomAD database, including 6,348 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.25 (6348 hom., cov: 32)
• Consequence: AMACR NM_014324.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0810

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 5-34007554-G-A is Benign according to our data. Variant chr5-34007554-G-A is described in ClinVar as [Benign]. Clinvar id is 1259415.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.466 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AMACR	NM_014324.6	c.247+219C>T		intron_variant		ENST00000335606.11	NP_055139.4
AMACR	NM_001167595.2	c.247+219C>T		intron_variant			NP_001161067.1
AMACR	NM_203382.3	c.247+219C>T		intron_variant			NP_976316.1
C1QTNF3-AMACR	NR_037951.1	n.765-1655C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AMACR	ENST00000335606.11	c.247+219C>T		intron_variant		1	NM_014324.6	ENSP00000334424.6
ENSG00000289791	ENST00000382068.3	c.247+219C>T		intron_variant		1		ENSP00000477108.1
C1QTNF3-AMACR	ENST00000382079.3	n.690-1655C>T		intron_variant		2		ENSP00000371511.3

Frequencies

GnomAD3 genomes AF: 0.255 AC: 38712 AN: 151996 Hom.: 6318 Cov.: 32

Gnomad AFR AF: 0.471

Gnomad AMI AF: 0.125

Gnomad AMR AF: 0.158

Gnomad ASJ AF: 0.212

Gnomad EAS AF: 0.164

Gnomad SAS AF: 0.225

Gnomad FIN AF: 0.171

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.171

Gnomad OTH AF: 0.240

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.255 AC: 38778 AN: 152114 Hom.: 6348 Cov.: 32 AF XY: 0.252 AC XY: 18769 AN XY: 74378

Gnomad4 AFR AF: 0.472

Gnomad4 AMR AF: 0.158

Gnomad4 ASJ AF: 0.212

Gnomad4 EAS AF: 0.164

Gnomad4 SAS AF: 0.224

Gnomad4 FIN AF: 0.171

Gnomad4 NFE AF: 0.171

Gnomad4 OTH AF: 0.236

Alfa AF: 0.219 Hom.: 595

Bravo AF: 0.265

Asia WGS AF: 0.193 AC: 673 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 11, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.7
DANN	Benign	0.70

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: rs34688; hg19: chr5-34007659;