rs773515

Variant names:

• chr9-91220650-C-T
• rs773515
• NM_001698.3:c.843+155G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001698.3(AUH):​c.843+155G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.509 in 152,136 control chromosomes in the GnomAD database, including 22,153 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.51 (22153 hom., cov: 33)
• Consequence: AUH NM_001698.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.317
• Publications: 4 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 9-91220650-C-T is Benign according to our data. Variant chr9-91220650-C-T is described in ClinVar as [Benign]. Clinvar id is 683368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.635 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AUH	NM_001698.3	c.843+155G>A		intron_variant	Intron 7 of 9	ENST00000375731.9	NP_001689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AUH	ENST00000375731.9	c.843+155G>A		intron_variant	Intron 7 of 9	1	NM_001698.3	ENSP00000364883.5
AUH	ENST00000303617.5	c.756+155G>A		intron_variant	Intron 6 of 8	1		ENSP00000307334.5
AUH	ENST00000473695.1	n.115+155G>A		intron_variant	Intron 1 of 2	2

Frequencies

GnomAD3 genomes AF: 0.510 AC: 77474 AN: 152018 Hom.: 22155 Cov.: 33

Gnomad AFR AF: 0.243

Gnomad AMI AF: 0.608

Gnomad AMR AF: 0.644

Gnomad ASJ AF: 0.504

Gnomad EAS AF: 0.346

Gnomad SAS AF: 0.544

Gnomad FIN AF: 0.574

Gnomad MID AF: 0.513

Gnomad NFE AF: 0.640

Gnomad OTH AF: 0.539

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

GnomAD4 genome AF: 0.509 AC: 77490 AN: 152136 Hom.: 22153 Cov.: 33 AF XY: 0.507 AC XY: 37739 AN XY: 74368

African (AFR) AF: 0.243 AC: 10082 AN: 41492

American (AMR) AF: 0.644 AC: 9850 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.504 AC: 1750 AN: 3470

East Asian (EAS) AF: 0.345 AC: 1788 AN: 5176

South Asian (SAS) AF: 0.545 AC: 2629 AN: 4824

European-Finnish (FIN) AF: 0.574 AC: 6071 AN: 10584

Middle Eastern (MID) AF: 0.497 AC: 146 AN: 294

European-Non Finnish (NFE) AF: 0.640 AC: 43491 AN: 67982

Other (OTH) AF: 0.535 AC: 1131 AN: 2114

Alfa AF: 0.599 Hom.: 35673

Bravo AF: 0.497

Asia WGS AF: 0.410 AC: 1424 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.3
DANN	Benign	0.55
PhyloP100		0.32
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: rs773515; hg19: chr9-93982932;