1-155610313-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_018116.4(MSTO1):c.65C>A(p.Ala22Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 26)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MSTO1 NM_018116.4 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.15

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.808
• PP5: Variant 1-155610313-C-A is Pathogenic according to our data. Variant chr1-155610313-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1693163.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSTO1	NM_018116.4	c.65C>A	p.Ala22Glu	missense_variant	1/14	ENST00000245564.8
LOC105371452	XR_922171.2	n.77-421G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSTO1	ENST00000245564.8	c.65C>A	p.Ala22Glu	missense_variant	1/14	1	NM_018116.4	P1
	ENST00000456382.2	n.68G>T		non_coding_transcript_exon_variant	1/2	5

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 912646 Hom.: 0 Cov.: 12 AF XY: 0.00 AC XY: 0 AN XY: 457514

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 26

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

See cases Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Laboratory of Genetics in Ophthalmology, Institut Imagine

Jun 17, 2022

The c.65C>A (p.22AlaGlu) variant in MSTO1 is absent from large population studies. It has been identified in compound heterozygosity with the c.220+5 splice variant (induces exon skipping; nonsense-mediated mRNA decay highly suspected from mRNA analysis in patient cells) in three siblings affected with typical MSTO1-associated myopathy, cerebellar atrophy and corticospinal involvement associated with a previously unreported optic neuropathy responsible for a profound central visual loss. Biallelism has been experimentally demonstrated. Multiple line of computational evidence support deleterious effect of the variant. In summary, the variant meets criteria to be classified as likely pathogenic based upon phenotype, family history, segregation studies, absence from controls and computational predictions. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
Cadd	Pathogenic	31
Dann	Uncertain	1.0
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Benign	0.065	D
MetaRNN	Pathogenic	0.81	D;D;D
MetaSVM	Uncertain	-0.086	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.88	D
Polyphen		1.0	.;D;.
Vest4		0.80, 0.77
MutPred		0.68		Gain of catalytic residue at W24 (P = 0.1955);Gain of catalytic residue at W24 (P = 0.1955);Gain of catalytic residue at W24 (P = 0.1955);
MVP		0.76
MPC		3.6
ClinPred		0.97	D
GERP RS		3.3
Varity_R		0.42
gMVP		0.76

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-155580104;