rs878853060

Variant names:

• chrM-9861-T-C
• rs878853060
• ENST00000362079.2:c.655T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4 BP6_Very_Strong BS2

The ENST00000362079.2(MT-CO3):​c.655T>C​(p.Phe219Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 7/11 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F219Y) has been classified as Likely benign.

• Frequency: Mitomap GenBank: 𝑓 0.0021 (AC: 127)
• Consequence: MT-CO3 ENST00000362079.2 missense
• Scores: Apogee2 Benign 0.041
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2 AD
• Conservation: PhyloP100: -0.824
• Publications: 3 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-ND3 (HGNC:7458): (mitochondrially encoded NADH dehydrogenase 3) Enables NADH dehydrogenase (ubiquinone) activity. Involved in mitochondrial electron transport, NADH to ubiquinone. Part of mitochondrial respiratory chain complex I. Implicated in Leber hereditary optic neuropathy; Leigh disease; and Parkinson's disease. [provided by Alliance of Genome Resources, Apr 2022]

TRNG (HGNC:7486): (mitochondrially encoded tRNA glycine)

TRNG Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Apogee2 supports a benign effect, 0.0412673 < 0.5 .
• BP6: Variant M-9861-T-C is Benign according to our data. Variant chrM-9861-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 235537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomadMitoHomoplasmic at 120

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

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

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT-CO3	ENST00000362079.2	TSL:6	c.655T>C	p.Phe219Leu	missense	Exon 1 of 1	ENSP00000354982.2	P00414
	MT-ND3	ENST00000361227.2	TSL:6	c.-198T>C		upstream_gene	N/A	ENSP00000355206.2	P03897
	MT-TG	ENST00000387429.1	TSL:6	n.-130T>C		upstream_gene	N/A

Frequencies

Mitomap GenBank AF: 0.0021 AC: 127

Gnomad homoplasmic AF: 0.0021 AC: 120 AN: 56410

Gnomad heteroplasmic AF: 0.00012 AC: 7 AN: 56410

Alfa AF: 0.00223 Hom.: 10

Mitomap

Disease(s): AD

Status: Reported

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Apogee2	Benign	0.041
Hmtvar	Benign	0.10
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.51	T
DEOGEN2	Benign	0.011	T
LIST_S2	Benign	0.53	T
MutationAssessor	Benign	-1.8	N
PhyloP100		-0.82
PROVEAN	Benign	2.7	N
Sift	Benign	0.069	T
Sift4G	Benign	1.0	T
GERP RS		-3.3
Varity_R		0.12
Mutation Taster		=96/4	polymorphism

Other links and lift over

dbSNP: rs878853060; hg19: chrM-9862;