9-91355976-C-T

Variant names:

• chr9-91355976-C-T
• rs10991898
• NM_001698.3:c.331-6G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001698.3(AUH):​c.331-6G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.103 in 1,608,060 control chromosomes in the GnomAD database, including 9,082 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.087 (655 hom., cov: 32)
  • Exomes 𝑓: 0.10 (8427 hom.)
• Consequence: AUH NM_001698.3 splice_region, intron
• Scores: Splicing: ADA: 0.00006482
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.112
• Publications: 11 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 9-91355976-C-T is Benign according to our data. Variant chr9-91355976-C-T is described in ClinVar as Benign. ClinVar VariationId is 258170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.167 is higher than 0.05.

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.331-6G>A		splice_region intron	N/A	NP_001689.1	Q13825-1
	AUH	NM_001306190.2		c.331-6G>A		splice_region intron	N/A	NP_001293119.1	Q13825-2
	AUH	NM_001351431.2		c.4-6G>A		splice_region intron	N/A	NP_001338360.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AUH	ENST00000375731.9	TSL:1 MANE Select	c.331-6G>A		splice_region intron	N/A	ENSP00000364883.5	Q13825-1
	AUH	ENST00000303617.5	TSL:1	c.331-6G>A		splice_region intron	N/A	ENSP00000307334.5	Q13825-2
	AUH	ENST00000895926.1		c.361-6G>A		splice_region intron	N/A	ENSP00000565985.1

Frequencies

GnomAD3 genomes AF: 0.0874 AC: 13083 AN: 149700 Hom.: 653 Cov.: 32

Gnomad AFR AF: 0.0416

Gnomad AMI AF: 0.0553

Gnomad AMR AF: 0.104

Gnomad ASJ AF: 0.131

Gnomad EAS AF: 0.176

Gnomad SAS AF: 0.107

Gnomad FIN AF: 0.0741

Gnomad MID AF: 0.175

Gnomad NFE AF: 0.102

Gnomad OTH AF: 0.105

GnomAD2 exomes AF: 0.110 AC: 27457 AN: 250486 AF XY: 0.111

Gnomad AFR exome AF: 0.0392

Gnomad AMR exome AF: 0.120

Gnomad ASJ exome AF: 0.132

Gnomad EAS exome AF: 0.187

Gnomad FIN exome AF: 0.0785

Gnomad NFE exome AF: 0.110

Gnomad OTH exome AF: 0.114

GnomAD4 exome AF: 0.105 AC: 153082 AN: 1458244 Hom.: 8427 Cov.: 31 AF XY: 0.105 AC XY: 76265 AN XY: 725616

African (AFR) AF: 0.0395 AC: 1319 AN: 33394

American (AMR) AF: 0.123 AC: 5478 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.131 AC: 3409 AN: 26078

East Asian (EAS) AF: 0.146 AC: 5793 AN: 39584

South Asian (SAS) AF: 0.0988 AC: 8504 AN: 86076

European-Finnish (FIN) AF: 0.0789 AC: 4210 AN: 53338

Middle Eastern (MID) AF: 0.185 AC: 1069 AN: 5764

European-Non Finnish (NFE) AF: 0.105 AC: 116718 AN: 1109052

Other (OTH) AF: 0.109 AC: 6582 AN: 60254

GnomAD4 genome AF: 0.0874 AC: 13097 AN: 149816 Hom.: 655 Cov.: 32 AF XY: 0.0868 AC XY: 6338 AN XY: 73004

African (AFR) AF: 0.0415 AC: 1688 AN: 40650

American (AMR) AF: 0.105 AC: 1579 AN: 15064

Ashkenazi Jewish (ASJ) AF: 0.131 AC: 451 AN: 3438

East Asian (EAS) AF: 0.176 AC: 903 AN: 5122

South Asian (SAS) AF: 0.107 AC: 505 AN: 4706

European-Finnish (FIN) AF: 0.0741 AC: 752 AN: 10146

Middle Eastern (MID) AF: 0.171 AC: 50 AN: 292

European-Non Finnish (NFE) AF: 0.102 AC: 6892 AN: 67416

Other (OTH) AF: 0.109 AC: 227 AN: 2078

Alfa AF: 0.0960 Hom.: 401

Bravo AF: 0.0890

Asia WGS AF: 0.135 AC: 469 AN: 3472

EpiCase AF: 0.108

EpiControl AF: 0.114

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	4.5
DANN	Benign	0.65
PhyloP100		0.11
RBP_binding_hub_radar		0.67
RBP_regulation_power_radar		2.9
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000065
dbscSNV1_RF	Benign	0.0020
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: rs10991898; hg19: chr9-94118258;