9-91214288-C-T

Variant names:

• chr9-91214288-C-T
• rs1564001076
• NM_001698.3:c.*60G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001698.3(AUH):​c.*60G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000776 in 1,288,788 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000078 (0 hom.)
• Consequence: AUH NM_001698.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.570
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• 3-methylglutaconic aciduria type 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen

ENSG00000306114 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AUH	NM_001698.3	c.*60G>A		3_prime_UTR_variant	Exon 10 of 10	ENST00000375731.9	NP_001689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AUH	ENST00000375731.9	c.*60G>A		3_prime_UTR_variant	Exon 10 of 10	1	NM_001698.3	ENSP00000364883.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000776 AC: 10 AN: 1288788 Hom.: 0 Cov.: 19 AF XY: 0.00000932 AC XY: 6 AN XY: 644094

African (AFR) AF: 0.00 AC: 0 AN: 29508

American (AMR) AF: 0.00 AC: 0 AN: 39216

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24576

East Asian (EAS) AF: 0.00 AC: 0 AN: 36888

South Asian (SAS) AF: 0.0000380 AC: 3 AN: 78864

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47530

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5446

European-Non Finnish (NFE) AF: 0.00000617 AC: 6 AN: 972510

Other (OTH) AF: 0.0000184 AC: 1 AN: 54250

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

3-methylglutaconic aciduria type 1 Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.6
DANN	Benign	0.49
PhyloP100		-0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1564001076; hg19: chr9-93976570; COSMIC: COSV57864869; COSMIC: COSV57864869;