9-91325340-T-G

Position:

• chr9-91325340-T-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001698.3(AUH):​c.483A>C​(p.Ile161Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0999 in 1,613,346 control chromosomes in the GnomAD database, including 8,792 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1128 hom., cov: 32)
  • Exomes 𝑓: 0.098 (7664 hom.)
• Consequence: AUH NM_001698.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.636

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]

AUH (HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 9-91325340-T-G is Benign according to our data. Variant chr9-91325340-T-G is described in ClinVar as [Benign]. Clinvar id is 128520.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-91325340-T-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.636 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.17 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AUH	NM_001698.3	c.483A>C	p.Ile161Ile	synonymous_variant	4/10	ENST00000375731.9	NP_001689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AUH	ENST00000375731.9	c.483A>C	p.Ile161Ile	synonymous_variant	4/10	1	NM_001698.3	ENSP00000364883.5
AUH	ENST00000303617.5	c.419-27264A>C		intron_variant		1		ENSP00000307334.5
AUH	ENST00000478465.5	n.643A>C		non_coding_transcript_exon_variant	5/6	3

Frequencies

GnomAD3 genomes AF: 0.114 AC: 17393 AN: 152098 Hom.: 1126 Cov.: 32

Gnomad AFR AF: 0.174

Gnomad AMI AF: 0.129

Gnomad AMR AF: 0.0808

Gnomad ASJ AF: 0.115

Gnomad EAS AF: 0.0173

Gnomad SAS AF: 0.0505

Gnomad FIN AF: 0.0792

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.103

Gnomad OTH AF: 0.118

GnomAD3 exomes AF: 0.0839 AC: 21101 AN: 251374 Hom.: 1129 AF XY: 0.0824 AC XY: 11198 AN XY: 135858

Gnomad AFR exome AF: 0.179

Gnomad AMR exome AF: 0.0513

Gnomad ASJ exome AF: 0.118

Gnomad EAS exome AF: 0.0138

Gnomad SAS exome AF: 0.0469

Gnomad FIN exome AF: 0.0757

Gnomad NFE exome AF: 0.0996

Gnomad OTH exome AF: 0.0953

GnomAD4 exome AF: 0.0984 AC: 143807 AN: 1461130 Hom.: 7664 Cov.: 31 AF XY: 0.0966 AC XY: 70202 AN XY: 726888

Gnomad4 AFR exome AF: 0.180

Gnomad4 AMR exome AF: 0.0550

Gnomad4 ASJ exome AF: 0.121

Gnomad4 EAS exome AF: 0.0217

Gnomad4 SAS exome AF: 0.0500

Gnomad4 FIN exome AF: 0.0751

Gnomad4 NFE exome AF: 0.105

Gnomad4 OTH exome AF: 0.102

GnomAD4 genome AF: 0.114 AC: 17413 AN: 152216 Hom.: 1128 Cov.: 32 AF XY: 0.111 AC XY: 8278 AN XY: 74444

Gnomad4 AFR AF: 0.174

Gnomad4 AMR AF: 0.0807

Gnomad4 ASJ AF: 0.115

Gnomad4 EAS AF: 0.0172

Gnomad4 SAS AF: 0.0506

Gnomad4 FIN AF: 0.0792

Gnomad4 NFE AF: 0.103

Gnomad4 OTH AF: 0.116

Alfa AF: 0.100 Hom.: 1912

Bravo AF: 0.119

Asia WGS AF: 0.0450 AC: 158 AN: 3478

EpiCase AF: 0.104

EpiControl AF: 0.101

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 22, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

3-methylglutaconic aciduria type 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	6.7
DANN	Benign	0.78

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: rs7874056; hg19: chr9-94087622; COSMIC: COSV57863314;