rs202182817

Positions:

• chr9-91220918-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_001698.3(AUH):​c.730G>A​(p.Asp244Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000569 in 1,614,166 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 Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00040 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00059 (1 hom.)
• Consequence: AUH NM_001698.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 5.50

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_001698.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.105192006).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AUH	NM_001698.3	c.730G>A	p.Asp244Asn	missense_variant	7/10	ENST00000375731.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AUH	ENST00000375731.9	c.730G>A	p.Asp244Asn	missense_variant	7/10	1	NM_001698.3	P1
AUH	ENST00000303617.5	c.643G>A	p.Asp215Asn	missense_variant	6/9	1
AUH	ENST00000473695.1	n.2G>A		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes AF: 0.000401 AC: 61 AN: 152158 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000632

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000426 AC: 107 AN: 251394 Hom.: 1 AF XY: 0.000434 AC XY: 59 AN XY: 135864

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00118

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000449

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000587 AC: 858 AN: 1461890 Hom.: 1 Cov.: 31 AF XY: 0.000641 AC XY: 466 AN XY: 727246

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000335

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00141

Gnomad4 FIN exome AF: 0.000150

Gnomad4 NFE exome AF: 0.000610

Gnomad4 OTH exome AF: 0.000530

GnomAD4 genome AF: 0.000401 AC: 61 AN: 152276 Hom.: 0 Cov.: 33 AF XY: 0.000282 AC XY: 21 AN XY: 74454

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.000632

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000598 Hom.: 0

Bravo AF: 0.000400

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000420 AC: 51

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000709

EpiControl AF: 0.000652

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

3-methylglutaconic aciduria type 1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 23, 2022	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 244 of the AUH protein (p.Asp244Asn). This variant is present in population databases (rs202182817, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with AUH-related conditions. ClinVar contains an entry for this variant (Variation ID: 214146). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 18, 2022

The c.730G>A (p.D244N) alteration is located in exon 7 (coding exon 7) of the AUH gene. This alteration results from a G to A substitution at nucleotide position 730, causing the aspartic acid (D) at amino acid position 244 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Sep 14, 2018

p.Asp244Asn (GAT>AAT): c.730 G>A in exon 7 of the AUH gene (NM_001698.2). The D244N missense substitution has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The amino acid change is non-conservative as a negatively charged Aspartic Acid residue is replaced by an uncharged Asparagine residue. This change occurs at a position in the AUH protein that is conserved in mammals. A missense mutation at a nearby position (A240V) has been reported in association with 3-methylglutaconic aciduria type 1. In-silico analyses are not consistent in their predictions of whether or not D244N is damaging to the AUH protein. Therefore, based on the currently available information, it is unclear whether D244N is a disease-causing mutation or a rare benign variant. The variant is found in MITONUC-MITOP panel(s). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.45
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T;.
Eigen	Benign	-0.0098
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	0.53	N;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-2.3	N;N
REVEL	Uncertain	0.30
Sift	Benign	0.31	T;T
Sift4G	Benign	0.34	T;T
Polyphen		0.053	B;B
Vest4		0.50
MVP		0.81
MPC		0.40
ClinPred		0.039	T
GERP RS		3.9
Varity_R		0.31
gMVP		0.90

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

Other links and lift over

dbSNP: rs202182817; hg19: chr9-93983200; COSMIC: COSV57863399;