rs2853826

Variant names:

• chrM-10398-A-G
• rs2853826
• ENST00000361227.2:c.340A>G

Your query was ambiguous. Multiple possible variants found:

• chrM-10398-A-G
• chrM-10398-A-T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4 BP6_Very_Strong BA1

The ENST00000361227.2(MT-ND3):​c.340A>G​(p.Thr114Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 7/8 in silico tools predict 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. T114I) has been classified as Uncertain significance.

• Frequency: Mitomap GenBank: 𝑓 0.42 (AC: 25902)
• Consequence: MT-ND3 ENST00000361227.2 missense
• Scores: Apogee2 Benign 0.040
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 Invasive-Breast-Cancer-risk-factor-AD-PD-BD-lithium-response-Type-2-DM,PD-protective-factor-/-longevity-/-altered-cell-pH-/-metabolic-syndrome-/-breast-cancer-risk-/-Leigh-Syndrome-risk-/-ADHD-/-cognitive-decline-/-SCA2-age-of-onset-/-Fuchs-endothelial-corneal-dystrophy
• Conservation: PhyloP100: -0.338
• Publications: 188 publications found

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-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]

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

TRNR Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP4: Apogee2 supports a benign effect, 0.040168878 < 0.5 .
• BP6: Variant M-10398-A-G is Benign according to our data. Variant chrM-10398-A-G is described in ClinVar as Benign. ClinVar VariationId is 9713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: High frequency in mitomap database: 0.42369998

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ND3	unassigned_transcript_4808	c.340A>G	p.Thr114Ala	missense_variant	Exon 1 of 1
ND4L	unassigned_transcript_4810	c.-72A>G		upstream_gene_variant
TRNR	unassigned_transcript_4809	c.-7A>G		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-ND3	ENST00000361227.2	c.340A>G	p.Thr114Ala	missense_variant	Exon 1 of 1	6		ENSP00000355206.2
MT-ND4L	ENST00000361335.1	c.-72A>G		upstream_gene_variant		6		ENSP00000354728.1
MT-TR	ENST00000387439.1	n.-7A>G		upstream_gene_variant		6

Frequencies

Mitomap GenBank AF: 0.42 AC: 25902

Gnomad homoplasmic AF: 0.42 AC: 23506 AN: 56170

Gnomad heteroplasmic AF: 0.00014 AC: 8 AN: 56170

Alfa AF: 0.139 Hom.: 6986

Mitomap

Disease(s): Invasive-Breast-Cancer-risk-factor-AD-PD-BD-lithium-response-Type-2-DM,PD-protective-factor-/-longevity-/-altered-cell-pH-/-metabolic-syndrome-/-breast-cancer-risk-/-Leigh-Syndrome-risk-/-ADHD-/-cognitive-decline-/-SCA2-age-of-onset-/-Fuchs-endothelial-corneal-dystrophy

Status: Reported|-lineage-N-marker-except-hg-IJK,Reported|-lineage-L-&-M-marker+-also-hg-IJK

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Leigh syndrome Benign:1

Oct 17, 2019

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NC_012920.1:m.10398A>G (YP_003024033.1:p.Thr114Ala) 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: BA1 -

Parkinson disease, resistance to Benign:1

Feb 01, 2007

OMIM

Significance: protective

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Benign	0.040
Hmtvar	Benign	0.040
AlphaMissense	Benign	0.064
DEOGEN2	Benign	0.18	T
LIST_S2	Uncertain	0.96	D
MutationAssessor	Benign	-0.60	N
PhyloP100		-0.34
PROVEAN	Benign	-1.4	N
Sift	Benign	0.41	T
Sift4G	Benign	1.0	T
Mutation Taster		=97/3	polymorphism

Other links and lift over

dbSNP: rs2853826; hg19: chrM-10399;