chr1-155610494-C-A

Variant names:

• chr1-155610494-C-A
• NM_018116.4:c.154C>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PP3_Strong

The NM_018116.4(MSTO1):​c.154C>A​(p.Arg52Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R52G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 16)
  • Exomes 𝑓: 0.0000056 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MSTO1 NM_018116.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.47
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• mitochondrial myopathy-cerebellar ataxia-pigmentary retinopathy syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Broad Center for Mendelian Genomics, Ambry Genetics

LOC105371452 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.972

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018116.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSTO1	NM_018116.4	MANE Select	c.154C>A	p.Arg52Ser	missense	Exon 2 of 14	NP_060586.2
	MSTO1	NM_001256532.1		c.154C>A	p.Arg52Ser	missense	Exon 2 of 14	NP_001243461.1	Q9BUK6-2
	MSTO1	NM_001350772.1		c.154C>A	p.Arg52Ser	missense	Exon 2 of 14	NP_001337701.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSTO1	ENST00000245564.8	TSL:1 MANE Select	c.154C>A	p.Arg52Ser	missense	Exon 2 of 14	ENSP00000245564.3	Q9BUK6-1
	MSTO1	ENST00000368341.8	TSL:2	c.154C>A	p.Arg52Ser	missense	Exon 2 of 13	ENSP00000357325.4	Q9BUK6-7
	MSTO1	ENST00000490743.5	TSL:1	n.154C>A		non_coding_transcript_exon	Exon 2 of 13	ENSP00000476353.1	Q9BUK6-4

Frequencies

GnomAD3 genomes Cov.: 16

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000559 AC: 4 AN: 715624 Hom.: 0 Cov.: 9 AF XY: 0.00000539 AC XY: 2 AN XY: 371280

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 18968

American (AMR) AF: 0.00 AC: 0 AN: 32988

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18026

East Asian (EAS) AF: 0.00 AC: 0 AN: 33424

South Asian (SAS) AF: 0.00 AC: 0 AN: 60088

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32460

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2594

European-Non Finnish (NFE) AF: 0.00000831 AC: 4 AN: 481428

Other (OTH) AF: 0.00 AC: 0 AN: 35648

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000000000417111), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 16

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.093	T
Eigen	Benign	0.15
Eigen_PC	Benign	-0.071
FATHMM_MKL	Benign	0.58	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.038	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Pathogenic	3.3	M
PhyloP100		1.5
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-5.1	D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.81
MutPred		0.94		Gain of glycosylation at R52 (P = 0.0362)
MVP		0.75
MPC		3.5
ClinPred		0.99	D
GERP RS		2.3
PromoterAI		-0.012	Neutral
Varity_R		0.65
gMVP		0.85
Mutation Taster		=58/42	polymorphism

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

Other links and lift over

hg19: chr1-155580285;