rs202182817

Positions:

chr9-91220918-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_001698.3(AUH):c.730G>A(p.Asp244Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000569 in 1,614,166 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00040 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00059 ( 1 hom. )

Consequence

AUH
NM_001698.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 5.50

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:

AUH (HGNC:):

AUH links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1

In a chain Methylglutaconyl-CoA hydratase, mitochondrial (size 271) in uniprot entity AUHM_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_001698.3

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.105192006).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AUH	NM_001698.3 linkuse as main transcript	c.730G>A	p.Asp244Asn	missense_variant	7/10	ENST00000375731.9	NP_001689.1	Q13825-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
AUH	ENST00000375731.9 linkuse as main transcript	c.730G>A	p.Asp244Asn	missense_variant	7/10	1	NM_001698.3	ENSP00000364883.5	Q13825-1
AUH	ENST00000303617.5 linkuse as main transcript	c.643G>A	p.Asp215Asn	missense_variant	6/9	1		ENSP00000307334.5	Q13825-2
AUH	ENST00000473695.1 linkuse as main transcript	n.2G>A		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes

AF:

0.000401

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000632

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000426

AC:

107

AN:

251394

Hom.:

AF XY:

0.000434

AC XY:

AN XY:

135864

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.000347

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00118

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000449

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000587

AC:

858

AN:

1461890

Hom.:

Cov.:

AF XY:

0.000641

AC XY:

466

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000335

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00141

Gnomad4 FIN exome

AF:

0.000150

Gnomad4 NFE exome

AF:

0.000610

Gnomad4 OTH exome

AF:

0.000530

GnomAD4 genome

AF:

0.000401

AC:

AN:

152276

Hom.:

Cov.:

AF XY:

0.000282

AC XY:

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.000168

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.000632

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000598

Hom.:

Bravo

AF:

0.000400

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000420

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000709

EpiControl

AF:

0.000652

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

3-methylglutaconic aciduria type 1

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 23, 2022	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 244 of the AUH protein (p.Asp244Asn). This variant is present in population databases (rs202182817, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with AUH-related conditions. ClinVar contains an entry for this variant (Variation ID: 214146). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

AUH-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 03, 2024

The AUH c.730G>A variant is predicted to result in the amino acid substitution p.Asp244Asn. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.12% of alleles in individuals of South Asian descent in gnomAD, which may be too common to be an undocumented cause of disease. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 18, 2022

The c.730G>A (p.D244N) alteration is located in exon 7 (coding exon 7) of the AUH gene. This alteration results from a G to A substitution at nucleotide position 730, causing the aspartic acid (D) at amino acid position 244 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Sep 14, 2018

p.Asp244Asn (GAT>AAT): c.730 G>A in exon 7 of the AUH gene (NM_001698.2). The D244N missense substitution has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The amino acid change is non-conservative as a negatively charged Aspartic Acid residue is replaced by an uncharged Asparagine residue. This change occurs at a position in the AUH protein that is conserved in mammals. A missense mutation at a nearby position (A240V) has been reported in association with 3-methylglutaconic aciduria type 1. In-silico analyses are not consistent in their predictions of whether or not D244N is damaging to the AUH protein. Therefore, based on the currently available information, it is unclear whether D244N is a disease-causing mutation or a rare benign variant. The variant is found in MITONUC-MITOP panel(s). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.45

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

T;.

Eigen

Benign

-0.0098

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.91

D;D

M_CAP

Benign

0.031

MetaRNN

Benign

0.11

T;T

MetaSVM

Benign

-0.62

MutationAssessor

Benign

0.53

N;.

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-2.3

N;N

REVEL

Uncertain

0.30

Sift

Benign

0.31

T;T

Sift4G

Benign

0.34

T;T

Polyphen

0.053

B;B

Vest4

0.50

MVP

0.81

MPC

0.40

ClinPred

0.039

GERP RS

3.9

Varity_R

0.31

gMVP

0.90

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

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