rs1556423663

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chrM-9355-A-G
• chrM-9355-A-T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4 BP6_Moderate BS2

The ENST00000362079.2(MT-CO3):​c.149A>G​(p.Asn50Ser) 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 Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N50I) has been classified as Uncertain significance.

• Frequency: Mitomap GenBank: 𝑓 0.00040 (AC: 23)
• Consequence: MT-CO3 ENST00000362079.2 missense
• Scores: Apogee2 Benign 0.044
• Clinical Significance: Benign criteria provided, single submitter B:1 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: Benign. The variant received -7 ACMG points.

• BP4: Apogee2 supports a benign effect, 0.044117868 < 0.5 .
• BP6: Variant M-9355-A-G is Benign according to our data. Variant chrM-9355-A-G is described in ClinVar as Benign. ClinVar VariationId is 693155.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomadMitoHomoplasmic at 13

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COX3	unassigned_transcript_4806	c.149A>G	p.Asn50Ser	missense_variant	Exon 1 of 1
ATP6	unassigned_transcript_4805	c.*148A>G		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-CO3	ENST00000362079.2	c.149A>G	p.Asn50Ser	missense_variant	Exon 1 of 1	6		ENSP00000354982.2
MT-ATP6	ENST00000361899.2	c.*148A>G		downstream_gene_variant		6		ENSP00000354632.2

Frequencies

Mitomap GenBank AF: 0.00040 AC: 23

Gnomad homoplasmic AF: 0.00023 AC: 13 AN: 56429

Gnomad heteroplasmic AF: 0.000035 AC: 2 AN: 56429

Alfa AF: 0.000334 Hom.: 1

Mitomap

No disease associated.

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Leigh syndrome Benign:1

Oct 17, 2019

Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NC_012920.1:m.9355A>G (YP_003024032.1:p.Asn50Ser) variant in MTCO3 gene is interpretated to be a Benign variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Benign	0.044
Hmtvar	Benign	0.10
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.46	T
DEOGEN2	Benign	0.0055	T
LIST_S2	Benign	0.71	T
MutationAssessor	Benign	0.24	N
PhyloP100		0.21
PROVEAN	Benign	0.49	N
Sift	Uncertain	0.028	D
Sift4G	Benign	0.073	T
GERP RS		2.0
Varity_R		0.14
Mutation Taster		=91/9	polymorphism

Other links and lift over

dbSNP: rs1556423663; hg19: chrM-9356;