Genetic Variant AUH:p.Ala275Glu (chr9-91220824-G-T) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong

The NM_001698.3(AUH):c.824C>A(p.Ala275Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,614,016 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

AUH
NM_001698.3 missense

Scores

Clinical Significance

Not reported in ClinVar

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 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;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.961

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AUH	NM_001698.3 link	c.824C>A	p.Ala275Glu	missense_variant	Exon 7 of 10	ENST00000375731.9	NP_001689.1	Q13825-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
AUH	ENST00000375731.9 link	c.824C>A	p.Ala275Glu	missense_variant	Exon 7 of 10	1	NM_001698.3	ENSP00000364883.5	Q13825-1
AUH	ENST00000303617.5 link	c.737C>A	p.Ala246Glu	missense_variant	Exon 6 of 9	1		ENSP00000307334.5	Q13825-2
AUH	ENST00000473695.1 link	n.96C>A		non_coding_transcript_exon_variant	Exon 1 of 3	2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461820

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.39

T;.

Eigen

Pathogenic

0.77

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

D;D

M_CAP

Uncertain

0.22

MetaRNN

Pathogenic

0.96

D;D

MetaSVM

Pathogenic

0.86

MutationAssessor

Pathogenic

3.7

H;.

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-4.6

D;D

REVEL

Pathogenic

0.84

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;D

Vest4

0.91

MutPred

0.79

Gain of disorder (P = 0.1105);.;

MVP

0.84

MPC

1.0

ClinPred

1.0

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.99

gMVP

0.99

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over