rs748318386

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong

The NM_001698.3(AUH):c.824C>T(p.Ala275Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,614,016 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A275A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

AUH
NM_001698.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3U:1

Conservation

PhyloP100: 9.12

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1

In a chain Methylglutaconyl-CoA hydratase, mitochondrial (size 271) in uniprot entity AUHM_HUMAN there are 17 pathogenic changes around while only 1 benign (94%) in NM_001698.3

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 9-91220824-G-A is Pathogenic according to our data. Variant chr9-91220824-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 214149.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AUH	NM_001698.3 linkuse as main transcript	c.824C>T	p.Ala275Val	missense_variant	7/10	ENST00000375731.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AUH	ENST00000375731.9 linkuse as main transcript	c.824C>T	p.Ala275Val	missense_variant	7/10	1	NM_001698.3	P1	Q13825-1
AUH	ENST00000303617.5 linkuse as main transcript	c.737C>T	p.Ala246Val	missense_variant	6/9	1			Q13825-2
AUH	ENST00000473695.1 linkuse as main transcript	n.96C>T		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000438

AC:

AN:

251300

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135832

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000171

AC:

AN:

1461820

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000201

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1

Uncertain significance, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 14, 2024	This variant has been reported in an infant with an inborn error of metabolism (PMID 32778825). However, no functional data supporting the pathogenicity of this variant was provided. This variant has been reported in ClinVar (Variation ID: 214149). The overall minor allele frequency for this variant (rs748318386) is approximately 0.0041%. An in silico tool predicts that this variant may impact RNA splicing. Taken together, evidence is not sufficient to determine whether this variant is benign or pathogenic. Therefore, this variant is classified as a variant of uncertain significance. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 25, 2014	p.Ala275Val (GCG>GTG): c.824 C>T in exon 7 of the AUH gene (NM_001698.2). A c.824 C>T sequence change likely associated with 3-methylglutaconic aciduria type 1 was identified in the AUH gene. It has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. If the protein was transcribed normally, this would lead to the replacement of an Alanine codon (GCG) with a Valine codon (GTG) at amino acid position 275. However, the c.824 C>T nucleotide substitution most likely appears to result in an error in gene splicing. This substitution occurs 21 nucleotides upstream from the canonical GT splice donor site in intron 7. Multiple splice prediction models predict that this substitution creates a cryptic splice donor site that is stronger than the natural donor site. Use of the cryptic splice site is expected to lead to abnormal gene splicing which would be expected to create an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. Therefore, c.824 C>T is a strong candidate for a disease-causing mutation, however the possibility that it is a benign variant cannot be excluded. The variant is found in MGA-MITOP panel(s). -

Inborn genetic diseases

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 12, 2017

- -

3-methylglutaconic aciduria type 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Apr 24, 2023

This missense change has been observed in individual(s) with clinical features of 3-methylglutaconic aciduria (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt AUH protein function. ClinVar contains an entry for this variant (Variation ID: 214149). This variant is present in population databases (rs748318386, gnomAD 0.03%). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 275 of the AUH protein (p.Ala275Val). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Uncertain

0.065

BayesDel_noAF

Pathogenic

0.15

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

T;.

Eigen

Pathogenic

0.68

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;D

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.89

D;D

MetaSVM

Uncertain

0.69

MutationAssessor

Uncertain

2.1

M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-3.8

D;D

REVEL

Pathogenic

0.69

Sift

Uncertain

0.0010

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;D

Vest4

0.80

MutPred

0.75

Gain of ubiquitination at K270 (P = 0.0913);.;

MVP

0.78

MPC

0.90

ClinPred

0.91

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.89

gMVP

0.95

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.95

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.95

Position offset: 2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over