chr9-91214148-T-C

Variant names:

• chr9-91214148-T-C
• rs113687423
• NM_001698.3:c.*200A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001698.3(AUH):​c.*200A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0011 in 564,218 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0029 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00043 (1 hom.)
• Consequence: AUH NM_001698.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0340
• 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: G2P, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen

ENSG00000306114 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 9-91214148-T-C is Benign according to our data. Variant chr9-91214148-T-C is described in ClinVar as [Benign]. Clinvar id is 914655.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00289 (440/152366) while in subpopulation AFR AF = 0.00979 (407/41586). AF 95% confidence interval is 0.009. There are 2 homozygotes in GnomAd4. There are 214 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AUH	NM_001698.3	c.*200A>G		3_prime_UTR_variant	Exon 10 of 10	ENST00000375731.9	NP_001689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AUH	ENST00000375731.9	c.*200A>G		3_prime_UTR_variant	Exon 10 of 10	1	NM_001698.3	ENSP00000364883.5

Frequencies

GnomAD3 genomes AF: 0.00279 AC: 425 AN: 152248 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00948

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00150

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00287

GnomAD4 exome AF: 0.000432 AC: 178 AN: 411852 Hom.: 1 Cov.: 4 AF XY: 0.000363 AC XY: 80 AN XY: 220134

African (AFR) AF: 0.0106 AC: 125 AN: 11790

American (AMR) AF: 0.000764 AC: 15 AN: 19636

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13284

East Asian (EAS) AF: 0.00 AC: 0 AN: 26632

South Asian (SAS) AF: 0.0000900 AC: 4 AN: 44438

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24990

Middle Eastern (MID) AF: 0.000357 AC: 1 AN: 2802

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 244912

Other (OTH) AF: 0.00141 AC: 33 AN: 23368

GnomAD4 genome AF: 0.00289 AC: 440 AN: 152366 Hom.: 2 Cov.: 32 AF XY: 0.00287 AC XY: 214 AN XY: 74514

African (AFR) AF: 0.00979 AC: 407 AN: 41586

American (AMR) AF: 0.00157 AC: 24 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68032

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00128 Hom.: 0

Bravo AF: 0.00315

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

3-methylglutaconic aciduria type 1 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	6.6
DANN	Benign	0.43
PhyloP100		-0.034
Mutation Taster		=100/0	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: rs113687423; hg19: chr9-93976430;