22-50487701-C-T

Position:

• chr22-50487701-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_017584.6(MIOX):​c.136C>T​(p.Leu46Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,524 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MIOX NM_017584.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.73

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3358782).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MIOX	NM_017584.6	c.136C>T	p.Leu46Phe	missense_variant	3/10	ENST00000216075.11	NP_060054.4
MIOX	XM_011530705.3	c.136C>T	p.Leu46Phe	missense_variant	3/6		XP_011529007.1
MIOX	XM_047441443.1	c.136C>T	p.Leu46Phe	missense_variant	3/9		XP_047297399.1
MIOX	XM_005261925.5	c.-3C>T		5_prime_UTR_variant	2/9		XP_005261982.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MIOX	ENST00000216075.11	c.136C>T	p.Leu46Phe	missense_variant	3/10	1	NM_017584.6	ENSP00000216075.6
MIOX	ENST00000395732.7	c.136C>T	p.Leu46Phe	missense_variant	3/10	1		ENSP00000379081.3
MIOX	ENST00000395733.7	c.136C>T	p.Leu46Phe	missense_variant	3/8	1		ENSP00000379082.3
MIOX	ENST00000451761.1	c.121C>T	p.Leu41Phe	missense_variant	2/9	3		ENSP00000409894.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461524 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727074

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 31, 2024

The c.136C>T (p.L46F) alteration is located in exon 3 (coding exon 3) of the MIOX gene. This alteration results from a C to T substitution at nucleotide position 136, causing the leucine (L) at amino acid position 46 to be replaced by a phenylalanine (F). 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	Benign	0.29
BayesDel_addAF	Benign	0.010	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	.;T;.;.
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.92	D;D;D;D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.34	T;T;T;T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Pathogenic	3.0	M;M;.;.
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-2.4	N;N;N;N
REVEL	Uncertain	0.31
Sift	Uncertain	0.028	D;T;D;D
Sift4G	Uncertain	0.026	D;T;D;T
Polyphen		1.0	D;P;D;.
Vest4		0.41
MutPred		0.46		Gain of catalytic residue at L46 (P = 0.0117);Gain of catalytic residue at L46 (P = 0.0117);Gain of catalytic residue at L46 (P = 0.0117);.;
MVP		0.17
MPC		0.27
ClinPred		0.98	D
GERP RS		4.4
Varity_R		0.15
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1049083027; hg19: chr22-50926130;