chrM-10161-A-T

Position:

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

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
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]

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ACMG classification

Classification made for transcript

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 Protein UniProt

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MT-ND3ENST00000361227.2 linkuse as main transcriptc.103A>T p.Thr35Ser 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:
0.0
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
LINK: link

Submissions by phenotype

Mitochondrial disease Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingNew York Genome CenterFeb 15, 2022The 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; API