22-50489547-C-T

Position:

• chr22-50489547-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP3 BP4_Moderate BP6 BS2

The NM_017584.6(MIOX):​c.652C>T​(p.Arg218Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00183 in 1,612,612 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0019 (5 hom.)
• Consequence: MIOX NM_017584.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 3.83

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 6: AlphaMissense, BayesDel_noAF, Cadd, Dann, MutationAssessor, PROVEAN [when max_spliceai, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.1538158).
• BP6: Variant 22-50489547-C-T is Benign according to our data. Variant chr22-50489547-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 788341.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MIOX	NM_017584.6	c.652C>T	p.Arg218Trp	missense_variant	9/10	ENST00000216075.11	NP_060054.4
MIOX	XM_005261925.5	c.514C>T	p.Arg172Trp	missense_variant	8/9		XP_005261982.1
MIOX	XM_047441443.1	c.*48C>T		3_prime_UTR_variant	9/9		XP_047297399.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MIOX	ENST00000216075.11	c.652C>T	p.Arg218Trp	missense_variant	9/10	1	NM_017584.6	ENSP00000216075.6
MIOX	ENST00000395732.7	c.652C>T	p.Arg218Trp	missense_variant	9/10	1		ENSP00000379081.3
MIOX	ENST00000395733.7	c.619-201C>T		intron_variant		1		ENSP00000379082.3
MIOX	ENST00000451761.1	c.592C>T	p.Arg198Trp	missense_variant	8/9	3		ENSP00000409894.1

Frequencies

GnomAD3 genomes AF: 0.00129 AC: 196 AN: 152144 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00235

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00108 AC: 269 AN: 248956 Hom.: 0 AF XY: 0.00101 AC XY: 137 AN XY: 135406

Gnomad AFR exome AF: 0.000375

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000820

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00205

Gnomad OTH exome AF: 0.00148

GnomAD4 exome AF: 0.00189 AC: 2754 AN: 1460468 Hom.: 5 Cov.: 41 AF XY: 0.00179 AC XY: 1304 AN XY: 726566

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000353

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000153

Gnomad4 NFE exome AF: 0.00235

Gnomad4 OTH exome AF: 0.00172

GnomAD4 genome AF: 0.00129 AC: 196 AN: 152144 Hom.: 0 Cov.: 31 AF XY: 0.00125 AC XY: 93 AN XY: 74314

Gnomad4 AFR AF: 0.000410

Gnomad4 AMR AF: 0.000720

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00235

Gnomad4 OTH AF: 0.00191

Alfa AF: 0.00188 Hom.: 0

Bravo AF: 0.00128

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00174 AC: 15

ExAC AF: 0.00127 AC: 154

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00174

EpiControl AF: 0.00190

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 02, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 10, 2023

The c.652C>T (p.R218W) alteration is located in exon 9 (coding exon 9) of the MIOX gene. This alteration results from a C to T substitution at nucleotide position 652, causing the arginine (R) at amino acid position 218 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	0.89
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.63	D;.;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	1.0	D;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.15	T;T;T
MetaSVM	Uncertain	0.23	D
MutationAssessor	Pathogenic	3.5	H;.;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-7.3	D;D;D
REVEL	Uncertain	0.54
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.94
MVP		0.067
MPC		0.36
ClinPred		0.24	T
GERP RS		4.1
Varity_R		0.84
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs149138591; hg19: chr22-50927976;