rs622288

chr1-155612848-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP5 BP4

The NM_018116.4(MSTO1):c.971C>T(p.Thr324Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000384 in 1,613,770 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000038 (0 hom.)
• Consequence: MSTO1 NM_018116.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:1
• Conservation: PhyloP100: 2.90

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PP5: Variant 1-155612848-C-T is Pathogenic according to our data. Variant chr1-155612848-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 438833.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Likely_pathogenic=4, Uncertain_significance=1}. Variant chr1-155612848-C-T is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.10128847).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSTO1	NM_018116.4	c.971C>T	p.Thr324Ile	missense_variant	10/14	ENST00000245564.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSTO1	ENST00000245564.8	c.971C>T	p.Thr324Ile	missense_variant	10/14	1	NM_018116.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152208 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000359 AC: 9 AN: 250888 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135566

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000383 AC: 56 AN: 1461562 Hom.: 0 Cov.: 33 AF XY: 0.0000358 AC XY: 26 AN XY: 727098

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000342

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152208 Hom.: 0 Cov.: 30 AF XY: 0.0000269 AC XY: 2 AN XY: 74364

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Mitochondrial myopathy-cerebellar ataxia-pigmentary retinopathy syndrome Pathogenic:5

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 22, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 23, 2021	Variant summary: MSTO1 c.971C>T (p.Thr324Ile) results in a non-conservative amino acid change located in the DML1/Misato, tubulin domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 250888 control chromosomes (gnomAD). c.971C>T has been reported in the literature in four independent indviduals carrying a second MSTO1 variant, whose clinical features overlap with Mitochondrial Myopathy-Cerebellar Ataxia-Pigmentary Retinopathy Syndrome, including delayed motor and speech development, muscle weakness, unsteady gait/poor coordination, tremor, and abnormal EMG, MRI and/or muscle biopsy (Nasca_2017, Donkervoort_2019, Jiao_2020, Lee_2020). To our knowledge, no conclusive functional/experimental studies have been performed on the variant of interest. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000438833, PS1_S). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:28544275, PS3_S). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000043, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Undiagnosed Diseases Network, NIH	Dec 14, 2017	The c.971C>T (p.Thr324Ile) variant in MSTO1 is a nonsense variant. This variant was identified as a compound heterozygote with c.676C>T (p.Gln226Ter). The variant is seen in 13 individual in gnomAD as a heterozygote and has been reported in a similarly affected patient. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 25, 2023

In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29339779, 28544275, 31130378, 30684668, 31607746, 31463572, 35598585, 33222031, 35446979, 33672784, 36468072) -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 18, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	20
Dann	Benign	0.91
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.51	T;T;T
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.10	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;N;N
PrimateAI	Uncertain	0.48	T
Polyphen		0.034, 0.098	.;B;B
Vest4		0.25, 0.32
MutPred		0.39		Gain of catalytic residue at P326 (P = 0.0282);Gain of catalytic residue at P326 (P = 0.0282);.;
MVP		0.24
MPC		0.54
ClinPred		0.050	T
GERP RS		2.9
Varity_R		0.10
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs622288; hg19: chr1-155582639;