NM_001698.3:c.304T>A

Variant names:

• chr9-91356114-A-T
• rs1554721818
• NM_001698.3:c.304T>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_001698.3(AUH):​c.304T>A​(p.Ser102Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: AUH NM_001698.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.813

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 3 ACMG points.

• PM1: In a chain Methylglutaconyl-CoA hydratase, mitochondrial (size 271) in uniprot entity AUHM_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_001698.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3180681).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AUH	NM_001698.3	c.304T>A	p.Ser102Thr	missense_variant	Exon 2 of 10	ENST00000375731.9	NP_001689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AUH	ENST00000375731.9	c.304T>A	p.Ser102Thr	missense_variant	Exon 2 of 10	1	NM_001698.3	ENSP00000364883.5
AUH	ENST00000303617.5	c.304T>A	p.Ser102Thr	missense_variant	Exon 2 of 9	1		ENSP00000307334.5
AUH	ENST00000475023.1	n.8T>A		non_coding_transcript_exon_variant	Exon 1 of 3	2
AUH	ENST00000478465.5	n.464T>A		non_coding_transcript_exon_variant	Exon 3 of 6	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

3-methylglutaconic aciduria type 1 Uncertain:1

Sep 28, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine with threonine at codon 102 of the AUH protein (p.Ser102Thr). The serine residue is moderately conserved and there is a small physicochemical difference between serine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with AUH-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	18
DANN	Benign	0.71
DEOGEN2	Benign	0.15	T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.69	T;T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.32	T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	0.61	N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.9	N;N
REVEL	Benign	0.29
Sift	Uncertain	0.021	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		0.0010	B;B
Vest4		0.19
MutPred		0.80		Loss of disorder (P = 0.0724);Loss of disorder (P = 0.0724);
MVP		0.26
MPC		0.25
ClinPred		0.17	T
GERP RS		-4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.53
gMVP		0.68

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: rs1554721818; hg19: chr9-94118396;