chrM-10192-C-T

Position:

• chrM-10192-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM5 BP4 BP6_Moderate BS2

The ENST00000361227.2(MT-ND3):​c.134C>T​(p.Ser45Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts 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. S45P) has been classified as Pathogenic.

• Frequency: Mitomap GenBank: 𝑓 0.0017 (AC: 106)
• Consequence: MT-ND3 ENST00000361227.2 missense
• Scores: Apogee2 Benign 0.32
• Clinical Significance: Benign criteria provided, single submitter B:1 No linked disesase in Mitomap
• Conservation: PhyloP100: 2.70

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chrM-10191-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 9712.Status of the report is reviewed_by_expert_panel, 3 stars.
• BP4: Apogee2 supports a benign effect, 0.31512925 < 0.5 .
• BP6: Variant M-10192-C-T is Benign according to our data. Variant chrM-10192-C-T is described in ClinVar as [Benign]. Clinvar id is 693271.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomadMitoHomoplasmic at 81

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MT-ND3	ENST00000361227.2	c.134C>T	p.Ser45Phe	missense_variant	1/1			ENSP00000355206	P1

Frequencies

GnomAD4 exome Cov.: 0

We have no GnomAD4 genomes data on this position. Probably position not covered by the project.

Mitomap GenBank AF: 0.0017 AC: 106

Gnomad homoplasmic AF: 0.0014 AC: 81 AN: 56429

Gnomad heteroplasmic AF: 0.000035 AC: 2 AN: 56429

Alfa AF: 0.00110 Hom.: 9

Mitomap

No disease associated.

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Leigh syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Oct 17, 2019

The NC_012920.1:m.10192C>T (YP_003024033.1:p.Ser45Phe) variant in MTND3 gene is interpretated to be a Benign variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: BS1, BS2, BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Benign	0.32
Hmtvar	Benign	0.21
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.28	T
DEOGEN2	Uncertain	0.63	D
LIST_S2	Benign	0.22	T
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	1.0	N
PROVEAN	Uncertain	-3.5	D
Sift	Uncertain	0.021	D
Sift4G	Pathogenic	0.0	D
GERP RS		1.2
Varity_R		0.31

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1556423776; hg19: chrM-10193;