rs762798018

Positions:

chr1-155610270-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP5

The NM_001350776.1(MSTO1):c.-266G>A variant causes a 5 prime UTR premature start codon gain change. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 27)

Exomes 𝑓: 0.00022 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

MSTO1
NM_001350776.1 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:3

Conservation

PhyloP100: 4.08

Variant links:

Genes affected

MSTO1 (HGNC:29678): (misato mitochondrial distribution and morphology regulator 1) Involved in mitochondrion distribution. Located in cytosol and mitochondrial outer membrane. [provided by Alliance of Genome Resources, Apr 2022]

MSTO1 links:

MSTO1 (HGNC:):

MSTO1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PP5

Variant 1-155610270-G-A is Pathogenic according to our data. Variant chr1-155610270-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 438835.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSTO1	NM_018116.4 linkuse as main transcript	c.22G>A	p.Val8Met	missense_variant	1/14	ENST00000245564.8	NP_060586.2	Q9BUK6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSTO1	ENST00000245564.8 linkuse as main transcript	c.22G>A	p.Val8Met	missense_variant	1/14	1	NM_018116.4	ENSP00000245564.3		Q9BUK6-1
MSTO1	ENST00000368341.8 linkuse as main transcript	c.22G>A	p.Val8Met	missense_variant	1/13	2		ENSP00000357325.4		Q9BUK6-7

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

150766

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.0000488

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000660

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000190

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000296

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000202

AC:

AN:

123620

Hom.:

AF XY:

0.000257

AC XY:

AN XY:

66222

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000582

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000531

Gnomad SAS exome

AF:

0.000251

Gnomad FIN exome

AF:

0.000426

Gnomad NFE exome

AF:

0.000182

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000219

AC:

152

AN:

695628

Hom.:

Cov.:

AF XY:

0.000247

AC XY:

AN XY:

356964

show subpopulations

Gnomad4 AFR exome

AF:

0.000116

Gnomad4 AMR exome

AF:

0.0000804

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000316

Gnomad4 SAS exome

AF:

0.000398

Gnomad4 FIN exome

AF:

0.000229

Gnomad4 NFE exome

AF:

0.000218

Gnomad4 OTH exome

AF:

0.0000877

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000464

AC:

AN:

150880

Hom.:

Cov.:

AF XY:

0.0000679

AC XY:

AN XY:

73688

show subpopulations

Gnomad4 AFR

AF:

0.0000487

Gnomad4 AMR

AF:

0.0000659

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000190

Gnomad4 NFE

AF:

0.0000296

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00122

Hom.:

ExAC

AF:

0.0000636

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Mitochondrial myopathy-cerebellar ataxia-pigmentary retinopathy syndrome

Pathogenic:1Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	Same nucleotide change resulting in same amino acid change has been previously reported to be associated with MSTO1 related disorder (ClinVar ID: VCV000438835, PS1_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000175, PM2_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.644, PP3_P). Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline. -
Uncertain significance, no assertion criteria provided	literature only	OMIM	Aug 28, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	Jun 22, 2023	The observed missense c.22G>A(p.Val8Met) variant in MSTO1 gene has been reported in heterozygous state in individuals affected with mitochondrial myopathy (Gal A, et al., 2017). The p.Val8Met variant is present with 0.02% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Uncertain Significance / Pathogenic. Multiple lines of computational evidences (Polyphen - Probably damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid change at this position on MSTO1 gene is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Val at position 8 is changed to a Met changing protein sequence and it might alter its composition and physico-chemical properties. However, additional functional details will be required to prove the pathogenicity of this variant. For these reasons, this variant has been classified as Likely Pathogenic. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 16, 2023

Reported in the heterozygous state in a family with mitochondrial myopathy, ataxia, minor dysmorphisms, endocrine dysfunctions, and psychiatric symptoms (Gal et al., 2017); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 34426522, 33672784, 30684668, 29339779, 31604776, 36468072, 33222031, 28554942) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.69

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.040

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

.;T;.

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.95

D;D;D

M_CAP

Benign

0.052

MetaRNN

Uncertain

0.59

D;D;D

MetaSVM

Uncertain

-0.20

MutationAssessor

Uncertain

2.7

.;M;M

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-2.1

.;N;N

REVEL

Uncertain

0.64

Sift

Uncertain

0.0020

.;D;D

Sift4G

Uncertain

0.0050

.;D;D

Polyphen

1.0

.;D;.

Vest4

0.73, 0.70

MutPred

0.72

Gain of disorder (P = 0.0831);Gain of disorder (P = 0.0831);Gain of disorder (P = 0.0831);

MVP

0.78

MPC

3.3

ClinPred

0.20

GERP RS

3.3

Varity_R

0.18

gMVP

0.62

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