rs730880310

chr9-91361809-AC-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001698.3(AUH):c.80del(p.Ser27MetfsTer8) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 151,988 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: AUH NM_001698.3 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.0780

Genes affected

AUH (HGNC:890): (AU RNA binding methylglutaconyl-CoA hydratase) This gene encodes bifunctional mitochondrial protein that has both RNA-binding and hydratase activities. The encoded protein is a methylglutaconyl-CoA hydratase that catalyzes the hydration of 3-methylglutaconyl-CoA to 3-hydroxy-3-methyl-glutaryl-CoA, a critical step in the leucine degradation pathway. This protein also binds AU-rich elements (AREs) found in the 3' UTRs of rapidly decaying mRNAs including c-fos, c-myc and granulocyte/ macrophage colony stimulating factor. ARE elements are involved in directing RNA to rapid degradation and deadenylation. This protein is localizes to the mitochondrial matrix and the inner mitochondrial membrane and may be involved in mitochondrial protein synthesis. Mutations in this gene are the cause of 3-methylglutaconic aciduria, type I. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2015]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 26 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-91361809-AC-A is Pathogenic according to our data. Variant chr9-91361809-AC-A is described in ClinVar as [Pathogenic]. Clinvar id is 9058.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr9-91361809-AC-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AUH	NM_001698.3	c.80del	p.Ser27MetfsTer8	frameshift_variant	1/10	ENST00000375731.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AUH	ENST00000375731.9	c.80del	p.Ser27MetfsTer8	frameshift_variant	1/10	1	NM_001698.3	P1
AUH	ENST00000303617.5	c.80del	p.Ser27MetfsTer8	frameshift_variant	1/9	1
AUH	ENST00000478465.5	n.78del		non_coding_transcript_exon_variant	1/6	3

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151988 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000479

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151988 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74276

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000479

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

3-methylglutaconic aciduria type 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 21, 2010

- -

Computational scores

Source: dbNSFP v4.3

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: rs730880310; hg19: chr9-94124091;