9-91214417-T-A

Variant names:

• chr9-91214417-T-A
• rs530710210
• NM_001698.3:c.951A>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_001698.3(AUH):​c.951A>T​(p.Pro317Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000106 in 1,607,680 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (1 hom.)
• Consequence: AUH NM_001698.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 1.12
• 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

ENSG00000306114 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 9-91214417-T-A is Benign according to our data. Variant chr9-91214417-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 367476.
• BP7: Synonymous conserved (PhyloP=1.12 with no splicing effect.

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.951A>T	p.Pro317Pro	synonymous	Exon 10 of 10	NP_001689.1	Q13825-1
	AUH	NM_001306190.2		c.864A>T	p.Pro288Pro	synonymous	Exon 9 of 9	NP_001293119.1	Q13825-2
	AUH	NM_001351431.2		c.624A>T	p.Pro208Pro	synonymous	Exon 11 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.951A>T	p.Pro317Pro	synonymous	Exon 10 of 10	ENSP00000364883.5	Q13825-1
	AUH	ENST00000303617.5	TSL:1	c.864A>T	p.Pro288Pro	synonymous	Exon 9 of 9	ENSP00000307334.5	Q13825-2
	AUH	ENST00000895926.1		c.981A>T	p.Pro327Pro	synonymous	Exon 11 of 11	ENSP00000565985.1

Frequencies

GnomAD3 genomes AF: 0.0000525 AC: 8 AN: 152236 Hom.: 0 Cov.: 32

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: 0.00165

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000192 AC: 46 AN: 239974 AF XY: 0.000246

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000169

GnomAD4 exome AF: 0.000111 AC: 162 AN: 1455326 Hom.: 1 Cov.: 30 AF XY: 0.000160 AC XY: 116 AN XY: 723700

African (AFR) AF: 0.00 AC: 0 AN: 33334

American (AMR) AF: 0.00 AC: 0 AN: 44342

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25928

East Asian (EAS) AF: 0.00 AC: 0 AN: 39564

South Asian (SAS) AF: 0.00172 AC: 147 AN: 85624

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52018

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5756

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1108648

Other (OTH) AF: 0.000183 AC: 11 AN: 60112

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152354 Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8 AN XY: 74498

African (AFR) AF: 0.00 AC: 0 AN: 41586

American (AMR) AF: 0.00 AC: 0 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

Asia WGS AF: 0.00173 AC: 6 AN: 3476

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	3-methylglutaconic aciduria type 1 (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	8.0
DANN	Benign	0.87
PhyloP100		1.1
Mutation Taster		=86/14	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: rs530710210; hg19: chr9-93976699;