1-155610565-G-C

Variant names:

• chr1-155610565-G-C
• rs1187504822
• NM_018116.4:c.220+5G>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3 PP5

The NM_018116.4(MSTO1):​c.220+5G>C variant causes a splice region, intron change. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000063 (0 hom., cov: 19)
  • Exomes 𝑓: 0.000076 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MSTO1 NM_018116.4 splice_region, intron
• Scores: Splicing: ADA: 0.9992
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 3.75

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]

LOC105371452 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 1-155610565-G-C is Pathogenic according to our data. Variant chr1-155610565-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1693164.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSTO1	NM_018116.4	c.220+5G>C		splice_region_variant, intron_variant	Intron 2 of 13	ENST00000245564.8	NP_060586.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSTO1	ENST00000245564.8	c.220+5G>C		splice_region_variant, intron_variant	Intron 2 of 13	1	NM_018116.4	ENSP00000245564.3
MSTO1	ENST00000368341.8	c.220+5G>C		splice_region_variant, intron_variant	Intron 2 of 12	2		ENSP00000357325.4

Frequencies

GnomAD3 genomes AF: 0.00 AC: 9 AN: 143732 Hom.: 0 Cov.: 19 FAILED QC

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000694

Gnomad ASJ AF: 0.00178

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000152

Gnomad OTH AF: 0.000513

GnomAD3 exomes AF: 0.0000325 AC: 2 AN: 61574 Hom.: 0 AF XY: 0.0000323 AC XY: 1 AN XY: 30986

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00127

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000761 AC: 57 AN: 749220 Hom.: 0 Cov.: 10 AF XY: 0.0000680 AC XY: 26 AN XY: 382472

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00253

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000243

Gnomad4 OTH exome AF: 0.000138

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000626 AC: 9 AN: 143732 Hom.: 0 Cov.: 19 AF XY: 0.0000720 AC XY: 5 AN XY: 69484

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000694

Gnomad4 ASJ AF: 0.00178

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000152

Gnomad4 OTH AF: 0.000513

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

See cases Pathogenic:1

Jun 17, 2022

Laboratory of Genetics in Ophthalmology, Institut Imagine

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

The c.220+5 variant in MSTO1 has been identified in compound heterozygosity with a likely pathogenic missense change (c.65A>G, p.Ala22Glu) in three siblings affected with typical MSTO1-assciated myoptahy, cerbellar atrophy and corticospinal track involvement and previously unreported bilateral optic neuropathy responsible for profound central visual loss. Biallelism has been demonstrated experimentaly. The change is known as rs1187504822 and is extremely rare with a minor allele frequency of 0.003%. The variant is predicted to abolish the donor splice-site of intron 2, induce exon skipping and introduce a premature termination codon in the mRNA. The mRNA encoded by the allele carrying the c.200+5G>C variant is undetectable in cells from affected individuals, suggesting nonsense-mediated mRNA decay. In summary, the c.220+5G>C variant meets our criteria to be classified as pathogenic based upon phenotype, family history, segregation studies, rarity in large population studies, computational evidence supporting deleterious effect and mRNA analysis. -

not provided Pathogenic:1

Aug 20, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Intronic variant directly or indirectly altering the +5 splice site in a gene for which loss of function is a known mechanism of disease, and splice predictors support a deleterious effect; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 37431816) -

Mitochondrial myopathy-cerebellar ataxia-pigmentary retinopathy syndrome Uncertain:1

May 31, 2023

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	21
DANN	Benign	0.80

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.59		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.59		Position offset: -5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1187504822; hg19: chr1-155580356;