NM_018116.4:c.100C>T

Variant names:

• chr1-155610440-C-T
• rs1673617254
• NM_018116.4:c.100C>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_018116.4(MSTO1):​c.100C>T​(p.Arg34*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000556 in 719,148 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 0.0000056 (0 hom.)
• Consequence: MSTO1 NM_018116.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.668
• 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: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-155610440-C-T is Pathogenic according to our data. Variant chr1-155610440-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 2571791.Status of the report is criteria_provided_single_submitter, 1 stars.

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.100C>T	p.Arg34*	stop_gained	Exon 2 of 14	NP_060586.2
	MSTO1	NM_001350776.1		c.-188C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 14	NP_001337705.1
	MSTO1	NM_001350777.1		c.-457C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 14	NP_001337706.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSTO1	ENST00000245564.8	TSL:1 MANE Select	c.100C>T	p.Arg34*	stop_gained	Exon 2 of 14	ENSP00000245564.3	Q9BUK6-1
	MSTO1	ENST00000368341.8	TSL:2	c.100C>T	p.Arg34*	stop_gained	Exon 2 of 13	ENSP00000357325.4	Q9BUK6-7
	MSTO1	ENST00000490743.5	TSL:1	n.100C>T		non_coding_transcript_exon	Exon 2 of 13	ENSP00000476353.1	Q9BUK6-4

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome AF: 0.00000556 AC: 4 AN: 719148 Hom.: 0 Cov.: 9 AF XY: 0.00000810 AC XY: 3 AN XY: 370248

⚠️ 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: 18776

American (AMR) AF: 0.0000933 AC: 3 AN: 32146

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17832

East Asian (EAS) AF: 0.00 AC: 0 AN: 32684

South Asian (SAS) AF: 0.00 AC: 0 AN: 58984

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31638

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2602

European-Non Finnish (NFE) AF: 0.00000205 AC: 1 AN: 488860

Other (OTH) AF: 0.00 AC: 0 AN: 35626

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00383038), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 21

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.048	T
BayesDel_noAF	Benign	-0.31
CADD	Pathogenic	26
DANN	Benign	0.97
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.012	N
PhyloP100		-0.67
Vest4		0.17
GERP RS		-5.9
PromoterAI		-0.087	Neutral
Mutation Taster		=45/155	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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

dbSNP: rs1673617254; hg19: chr1-155580231;