chrM-9377-A-G

Variant names:

• chrM-9377-A-G
• rs28380140
• ENST00000362079.2:c.171A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP7 BS1 BS2

The ENST00000362079.2(MT-CO3):​c.171A>G​(p.Trp57Trp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Mitomap GenBank: 𝑓 0.0084 (AC: 511)
• Consequence: MT-CO3 ENST00000362079.2 synonymous
• Clinical Significance: Not reported in ClinVar No linked disesase in Mitomap
• Conservation: PhyloP100: 1.61
• Publications: 11 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 -9 ACMG points.

• BP7: Synonymous conserved (PhyloP=1.61 with no splicing effect.
• BS1: High frequency in mitomap database: 0.0084
• BS2: High AC in GnomadMitoHomoplasmic at 493

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COX3	unassigned_transcript_4806	c.171A>G	p.Trp57Trp	synonymous_variant	Exon 1 of 1
ATP6	unassigned_transcript_4805	c.*170A>G		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-CO3	ENST00000362079.2	c.171A>G	p.Trp57Trp	synonymous_variant	Exon 1 of 1	6		ENSP00000354982.2
MT-ATP6	ENST00000361899.2	c.*170A>G		downstream_gene_variant		6		ENSP00000354632.2

Frequencies

Mitomap GenBank AF: 0.0084 AC: 511

Gnomad homoplasmic AF: 0.0087 AC: 493 AN: 56361

Gnomad heteroplasmic AF: 0.000071 AC: 4 AN: 56361

Alfa AF: 0.00610 Hom.: 268

Mitomap

No disease associated.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.6
Mutation Taster		=19/81	disease causing

Other links and lift over

dbSNP: rs28380140; hg19: chrM-9378; COSMIC: COSV62293526; COSMIC: COSV62293526;