M-9355-A-T

Variant names:

• chrM-9355-A-T
• rs1556423663
• ENST00000362079.2:c.149A>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000362079.2(MT-CO3):​c.149A>T​(p.Asn50Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 8/11 in silico tools predict a benign 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. N50S) has been classified as Benign.

• Frequency: Mitomap GenBank: 𝑓 0.0 (AC: 0)
• Consequence: MT-CO3 ENST00000362079.2 missense
• Scores: Apogee2 Benign 0.037
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2 No linked disesase in Mitomap
• Conservation: PhyloP100: 0.212
• Publications: 0 publications found

Genes affected

MT-CO3 (HGNC:7422): (mitochondrially encoded cytochrome c oxidase III) Predicted to enable electron transfer activity and oxidoreduction-driven active transmembrane transporter activity. Involved in respiratory chain complex IV assembly. Part of respiratory chain complex IV. Implicated in MELAS syndrome. [provided by Alliance of Genome Resources, Apr 2022]

MT-ATP6 (HGNC:7414): (mitochondrially encoded ATP synthase 6) Contributes to proton-transporting ATP synthase activity, rotational mechanism. Involved in mitochondrial ATP synthesis coupled proton transport. Part of mitochondrial proton-transporting ATP synthase complex. Implicated in Leber hereditary optic neuropathy; NARP syndrome; Parkinson's disease; multiple sclerosis; and systemic lupus erythematosus. [provided by Alliance of Genome Resources, Apr 2022]

MT-ATP6 Gene-Disease associations (from GenCC):

• Leigh syndrome

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
• NARP syndrome

  Inheritance: Mitochondrial Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
• familial infantile bilateral striatal necrosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• mitochondrial proton-transporting ATP synthase complex deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Leber hereditary optic neuropathy

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet
• maternally-inherited Leigh syndrome

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet
• maternally-inherited spastic paraplegia

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet
• periodic paralysis with later-onset distal motor neuropathy

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very low frequency in mitomap database: 0.0
• BP4: Apogee2 supports a benign effect, 0.036857087 < 0.5 .

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000362079.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT-CO3	ENST00000362079.2	TSL:6	c.149A>T	p.Asn50Ile	missense	Exon 1 of 1	ENSP00000354982.2
	MT-ATP6	ENST00000361899.2	TSL:6	c.*148A>T		downstream_gene	N/A	ENSP00000354632.2

Frequencies

Mitomap GenBank AF: 0.0 AC: 0

Mitomap

No disease associated.

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Cerebellar ataxia;C0311394:Difficulty walking;C0349588:Short stature;C1384666:Hearing impairment;C2242577:Oromandibular dystonia Uncertain:1

Jan 01, 2017

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sleep apnea;C0162557:Acute liver failure;C0392525:Nephrolithiasis;C0424551:Exercise intolerance;C0518656:Chronic fatigue;C1403035:Subcutaneous lipoma;C4021546:Abnormal mitochondria in muscle tissue;C4024664:Moderate sensorineural hearing impairment Uncertain:1

Jan 01, 2017

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Apogee2	Benign	0.037
Hmtvar	Benign	0.31
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.41	T
DEOGEN2	Benign	0.0036	T
LIST_S2	Benign	0.65	T
MutationAssessor	Benign	-1.2	N
PhyloP100		0.21
PROVEAN	Benign	2.1	N
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.58	T
GERP RS		2.0
Varity_R		0.39

Other links and lift over

dbSNP: rs1556423663; hg19: chrM-9356;