NM_001698.3:c.20C>A

Variant names:

• chr9-91361870-G-T
• rs863223911
• NM_001698.3:c.20C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001698.3(AUH):​c.20C>A​(p.Ala7Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000545 in 1,468,958 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A7V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000053 (0 hom.)
• Consequence: AUH NM_001698.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0220
• Publications: 0 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: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13759106).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001698.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AUH	NM_001698.3	MANE Select	c.20C>A	p.Ala7Glu	missense	Exon 1 of 10	NP_001689.1	Q13825-1
	AUH	NM_001306190.2		c.20C>A	p.Ala7Glu	missense	Exon 1 of 9	NP_001293119.1	Q13825-2
	AUH	NM_001351431.2		c.-378C>A		5_prime_UTR	Exon 1 of 11	NP_001338360.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AUH	ENST00000375731.9	TSL:1 MANE Select	c.20C>A	p.Ala7Glu	missense	Exon 1 of 10	ENSP00000364883.5	Q13825-1
	AUH	ENST00000303617.5	TSL:1	c.20C>A	p.Ala7Glu	missense	Exon 1 of 9	ENSP00000307334.5	Q13825-2
	AUH	ENST00000895926.1		c.20C>A	p.Ala7Glu	missense	Exon 1 of 11	ENSP00000565985.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151970 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000532 AC: 7 AN: 1316988 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 649488

African (AFR) AF: 0.00 AC: 0 AN: 26548

American (AMR) AF: 0.00 AC: 0 AN: 25118

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22812

East Asian (EAS) AF: 0.00 AC: 0 AN: 29388

South Asian (SAS) AF: 0.00 AC: 0 AN: 71786

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33730

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4300

European-Non Finnish (NFE) AF: 0.00000667 AC: 7 AN: 1048722

Other (OTH) AF: 0.00 AC: 0 AN: 54584

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151970 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74242

African (AFR) AF: 0.00 AC: 0 AN: 41424

American (AMR) AF: 0.0000655 AC: 1 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10550

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67954

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	3-methylglutaconic aciduria type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.076	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	14
DANN	Benign	0.78
DEOGEN2	Benign	0.22	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.47	T
M_CAP	Pathogenic	0.50	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.81	L
PhyloP100		0.022
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.73	N
REVEL	Benign	0.092
Sift	Uncertain	0.029	D
Sift4G	Uncertain	0.048	D
Polyphen		0.16	B
Vest4		0.30
MutPred		0.18		Loss of helix (P = 0.1299)
MVP		0.12
MPC		0.31
ClinPred		0.23	T
GERP RS		1.0
PromoterAI		-0.0062	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.075
gMVP		0.58
Mutation Taster		=94/6	polymorphism

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: rs863223911; hg19: chr9-94124152;