rs10991892

Variant names:

• chr9-91339880-A-G
• rs10991892
• NM_001698.3:c.419-14476T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001698.3(AUH):​c.419-14476T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0719 in 152,180 control chromosomes in the GnomAD database, including 685 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.072 (685 hom., cov: 32)
• Consequence: AUH NM_001698.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.970
• Publications: 3 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.253 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AUH	NM_001698.3	c.419-14476T>C		intron_variant	Intron 3 of 9	ENST00000375731.9	NP_001689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AUH	ENST00000375731.9	c.419-14476T>C		intron_variant	Intron 3 of 9	1	NM_001698.3	ENSP00000364883.5
AUH	ENST00000303617.5	c.418+16003T>C		intron_variant	Intron 3 of 8	1		ENSP00000307334.5
AUH	ENST00000478465.5	n.579-14476T>C		intron_variant	Intron 4 of 5	3

Frequencies

GnomAD3 genomes AF: 0.0719 AC: 10937 AN: 152062 Hom.: 685 Cov.: 32

Gnomad AFR AF: 0.0140

Gnomad AMI AF: 0.0603

Gnomad AMR AF: 0.0623

Gnomad ASJ AF: 0.0867

Gnomad EAS AF: 0.264

Gnomad SAS AF: 0.153

Gnomad FIN AF: 0.181

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0717

Gnomad OTH AF: 0.0697

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

GnomAD4 genome AF: 0.0719 AC: 10945 AN: 152180 Hom.: 685 Cov.: 32 AF XY: 0.0791 AC XY: 5885 AN XY: 74368

African (AFR) AF: 0.0139 AC: 578 AN: 41554

American (AMR) AF: 0.0622 AC: 952 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0867 AC: 301 AN: 3470

East Asian (EAS) AF: 0.264 AC: 1365 AN: 5162

South Asian (SAS) AF: 0.152 AC: 735 AN: 4820

European-Finnish (FIN) AF: 0.181 AC: 1908 AN: 10564

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0718 AC: 4880 AN: 67992

Other (OTH) AF: 0.0733 AC: 155 AN: 2116

Alfa AF: 0.0753 Hom.: 279

Bravo AF: 0.0607

Asia WGS AF: 0.180 AC: 626 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.58
DANN	Benign	0.64
PhyloP100		-0.97
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

Other links and lift over

dbSNP: rs10991892; hg19: chr9-94102162;