Genetic Variant MIOX:p.Arg107Trp (chr22-50488027-C-T) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_017584.6(MIOX):c.319C>T(p.Arg107Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000285 in 1,613,760 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

MIOX
NM_017584.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.99

Variant links:

Genes affected

MIOX (HGNC:14522): (myo-inositol oxygenase) Enables ferric iron binding activity and inositol oxygenase activity. Involved in inositol catabolic process. Predicted to be located in cytoplasm and inclusion body. [provided by Alliance of Genome Resources, Apr 2022]

MIOX links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.969

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MIOX	NM_017584.6 link	c.319C>T	p.Arg107Trp	missense_variant	Exon 4 of 10	ENST00000216075.11	NP_060054.4	Q9UGB7-1
MIOX	XM_005261925.5 link	c.181C>T	p.Arg61Trp	missense_variant	Exon 3 of 9		XP_005261982.1
MIOX	XM_011530705.3 link	c.319C>T	p.Arg107Trp	missense_variant	Exon 4 of 6		XP_011529007.1
MIOX	XM_047441443.1 link	c.319C>T	p.Arg107Trp	missense_variant	Exon 4 of 9		XP_047297399.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MIOX	ENST00000216075.11 link	c.319C>T	p.Arg107Trp	missense_variant	Exon 4 of 10	1	NM_017584.6	ENSP00000216075.6	Q9UGB7-1
MIOX	ENST00000395732.7 link	c.319C>T	p.Arg107Trp	missense_variant	Exon 4 of 10	1		ENSP00000379081.3	A6PVH2
MIOX	ENST00000395733.7 link	c.319C>T	p.Arg107Trp	missense_variant	Exon 4 of 8	1		ENSP00000379082.3	Q9UGB7-2
MIOX	ENST00000451761.1 link	c.304C>T	p.Arg102Trp	missense_variant	Exon 3 of 9	3		ENSP00000409894.1	A6PVH4

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000599

AC:

AN:

250372

Hom.:

AF XY:

0.0000590

AC XY:

AN XY:

135574

show subpopulations

Gnomad AFR exome

AF:

0.0000617

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000381

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000266

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000253

AC:

AN:

1461424

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

727014

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000895

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000171

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152336

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000579

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000741

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 04, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.319C>T (p.R107W) alteration is located in exon 4 (coding exon 4) of the MIOX gene. This alteration results from a C to T substitution at nucleotide position 319, causing the arginine (R) at amino acid position 107 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.76

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.42

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.63

.;D;.;.

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

0.99

D;D;D;D

M_CAP

Benign

0.071

MetaRNN

Pathogenic

0.97

D;D;D;D

MetaSVM

Uncertain

0.33

MutationAssessor

Pathogenic

3.5

H;H;.;.

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-8.0

D;D;D;D

REVEL

Pathogenic

0.73

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

D;D;D;.

Vest4

0.81

MutPred

0.93

Loss of disorder (P = 0.0148);Loss of disorder (P = 0.0148);Loss of disorder (P = 0.0148);.;

MVP

0.26

MPC

0.36

ClinPred

0.81

GERP RS

4.2

Varity_R

0.93

gMVP

0.87

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over