M-10161-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000361227.2(MT-ND3):c.103A>T(p.Thr35Ser) 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 Uncertain significance (★).

• Frequency: Mitomap GenBank: 𝑓 0.0 (AC: 0)
• Consequence: MT-ND3 ENST00000361227.2 missense
• Scores: Apogee2 Benign 0.060
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 No linked disesase in Mitomap
• Conservation: PhyloP100: 1.95

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very low frequency in mitomap database: 0.0
• BP4: Apogee2 supports a benign effect, 0.060099766 < 0.5 .

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MT-ND3	ENST00000361227.2	c.103A>T	p.Thr35Ser	missense_variant	1/1			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: 0.0 AC: 0

Gnomad homoplasmic AF: 0.0 AC: 0 AN: 56433

Gnomad heteroplasmic AF: 0.000018 AC: 1 AN: 56433

Mitomap

No disease associated.

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Mitochondrial disease Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Feb 15, 2022

The m.10161A>T variant in the mitochondrial genome has not previously been reported in the literature nor public variant repositories (ClinVar and LOVD). It has been observed in one individual at 63% heteroplasmy level in gnomAD v3.1.2 dataset while it is absent in MitoMap database, suggesting it is not a common benign variant in the populations represented in those databases. The m.10161A>T variant is located in MT-ND3, and is predicted to replace a threonine amino acid with serine at codon 35 (p.(Thr35Ser)). This variant was detected at 25.8% heteroplasmy level (1307/5054reads) in this individual and at 11% heteroplasmy level (649/5859reads) in their mother. The affected residue (p.Thr35) is not evolutionarily conserved, and in silico predictions are not in favor of damaging effect (APOGEE score = 0.3); however, there are no functional studies to support or refute these predictions. A nearby m.10158T>C p.(Ser34Pro) variant has been curated as pathogenic for primary mitochondrial disease including Leigh syndrome by ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel (ClinVar ID: 9714). Based on available evidence this maternally inherited mitochondrial m.10161A>T p.(Thr35Ser) variant identified in MT-ND3 is classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Benign	0.060
Hmtvar	Benign	0.090
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.32	T
DEOGEN2	Benign	0.17	T
LIST_S2	Benign	0.65	T
MutationAssessor	Benign	-1.2	N
MutationTaster	Benign	1.0	N
PROVEAN	Benign	1.8	N
Sift	Benign	0.95	T
Sift4G	Benign	1.0	T
GERP RS		3.7
Varity_R		0.17

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrM-10162;