Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 1P and 12B. PP3BP6_Very_StrongBS2

The ENST00000361227.2(MT-ND3):c.179T>C(p.Ile60Thr) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic 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. I60V) has been classified as Uncertain significance.

Frequency

Mitomap GenBank:

𝑓 0.0016 ( AC: 100 )

Consequence

MT-ND3
ENST00000361227.2 missense

Scores

Apogee2

Pathogenic

0.67

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2O:1

LHON

Conservation

PhyloP100: 7.73

Publications

1 publications found

Variant links:

Genes affected

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]

MT-ND3 links:

MT-ND4L (HGNC:7460): (mitochondrially encoded NADH 4L dehydrogenase) Predicted to enable NADH dehydrogenase (ubiquinone) activity. Predicted to be located in mitochondrial inner membrane. Implicated in Leber hereditary optic neuropathy and diabetes mellitus. [provided by Alliance of Genome Resources, Apr 2022]

MT-ND4L links:

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-CO3 links:

TRNR (HGNC:7496): (mitochondrially encoded tRNA arginine)

TRNR links:

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

TRNG Gene-Disease associations (from GenCC):

mitochondrial disease
Inheritance: Mitochondrial Classification: MODERATE Submitted by: ClinGen

TRNG links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

PP3

Apogee2 supports a deletorius effect, 0.66612965 >= 0.5 .

BP6

Variant M-10237-T-C is Benign according to our data. Variant chrM-10237-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 65508.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomadMitoHomoplasmic at 101

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000361227.2. 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MT-ND3	ENST00000361227.2	TSL:6	c.179T>C	p.Ile60Thr	missense	Exon 1 of 1	ENSP00000355206.2
MT-ND4L	ENST00000361335.1	TSL:6	c.-233T>C		upstream_gene	N/A	ENSP00000354728.1
MT-CO3	ENST00000362079.2	TSL:6	c.*247T>C		downstream_gene	N/A	ENSP00000354982.2

Frequencies

Mitomap GenBank

AF:

0.0016

AC:

100

Gnomad homoplasmic

AF:

0.0018

AC:

101

AN:

56415

Gnomad heteroplasmic

AF:

0.00016

AC:

AN:

56415

Alfa

AF:

0.000557

Hom.:

Mitomap

Disease(s): LHON

Status: Reported

Publication(s):

12227465

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Leigh syndrome (1)

not specified (1)

Leber optic atrophy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

Apogee2

Pathogenic

0.67

Hmtvar

Pathogenic

0.77

AlphaMissense

Pathogenic

0.76

BayesDel_addAF

Benign

-0.090

DEOGEN2

Uncertain

0.74

LIST_S2

Benign

0.78

MutationAssessor

Pathogenic

3.2

PhyloP100

7.7

PROVEAN

Pathogenic

-4.7

Sift

Uncertain

0.0060

Sift4G

Pathogenic

0.0

GERP RS

5.1

Varity_R

0.48

Mutation Taster

=68/32

polymorphism

(source)

Publications

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rs1556423787

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Mitomap

ClinVar

ClinVar submissions as Germline

Computational scores

Publications

Other links and lift over