Genetic Variant NM_018116.4:c.1A>C (chr1-155610249-A-C) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP5_Moderate

The NM_018116.4(MSTO1):c.1A>C(p.Met1?) variant causes a initiator codon change. The variant allele was found at a frequency of 0.0000264 in 151,766 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 28)

Consequence

MSTO1
NM_018116.4 initiator_codon

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 3.73

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:

ENSG00000232519 (HGNC:):

ENSG00000232519 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 5 pathogenic variants. Next in-frame start position is after 70 codons. Genomic position: 155610548. Lost 0.121 part of the original CDS.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-155610249-A-C is Pathogenic according to our data. Variant chr1-155610249-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2229213.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSTO1	NM_018116.4 link	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 14	ENST00000245564.8	NP_060586.2	Q9BUK6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSTO1	ENST00000245564.8 link	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 14	1	NM_018116.4	ENSP00000245564.3		Q9BUK6-1
MSTO1	ENST00000368341.8 link	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 13	2		ENSP00000357325.4		Q9BUK6-7

Frequencies

GnomAD3 genomes

AF:

0.0000264

AC:

AN:

151766

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000968

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000988

AC:

AN:

101208

Hom.:

AF XY:

0.00

AC XY:

AN XY:

53608

show subpopulations

Gnomad AFR exome

AF:

0.000114

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

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

Cov.:

GnomAD4 genome

AF:

0.0000264

AC:

AN:

151766

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74128

show subpopulations

Gnomad4 AFR

AF:

0.0000968

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Pathogenic:1

Feb 18, 2021

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1A>C (p.M1?) alteration is located in coding exon 1 of the MSTO1 gene and results from an A to C substitution at nucleotide position 1. This alters the methionine residue at the initiation codon (ATG). Sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. Based on data from the Genome Aggregation Database (gnomAD) database, the MSTO1 c.1A>C alteration was observed in 0% (1/101208) of total alleles studied. This amino acid position is highly conserved in available vertebrate species. Based on the available evidence, this alteration is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.22

CADD

Uncertain

DANN

Benign

0.95

DEOGEN2

Benign

0.0071

.;T;.

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.22

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.90

D;D;D

M_CAP

Benign

0.079

MetaRNN

Uncertain

0.58

D;D;D

MetaSVM

Benign

-0.90

PROVEAN

Benign

-1.3

.;N;N

REVEL

Benign

0.28

Sift

Pathogenic

0.0

.;D;D

Sift4G

Pathogenic

0.0

.;D;D

Polyphen

0.95

.;P;.

Vest4

0.81, 0.81

MutPred

0.50

Loss of catalytic residue at M1 (P = 0.1244);Loss of catalytic residue at M1 (P = 0.1244);Loss of catalytic residue at M1 (P = 0.1244);

MVP

0.37

ClinPred

0.99

GERP RS

3.3

Varity_R

0.96

gMVP

0.56

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