M-3338-T-C

Variant names:

• chrM-3338-T-C
• rs201969351
• ENST00000361390.2:c.32T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4 BP6_Very_Strong BS2

The ENST00000361390.2(MT-ND1):​c.32T>C​(p.Val11Ala) variant causes a missense change. In-silico tool predicts a benign 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. V11I) has been classified as Benign.

• Frequency: Mitomap GenBank: 𝑓 0.0021 (AC: 126)
• Consequence: MT-ND1 ENST00000361390.2 missense
• Scores: Apogee2 Benign 0.10
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3 No linked disesase in Mitomap
• Conservation: PhyloP100: 4.72
• Publications: 7 publications found

Genes affected

MT-ND1 (HGNC:7455): (mitochondrially encoded NADH dehydrogenase 1) Enables NADH dehydrogenase (ubiquinone) activity. Involved in mitochondrial electron transport, NADH to ubiquinone and mitochondrial respiratory chain complex I assembly. Located in mitochondrial membrane. Part of mitochondrial respiratory chain complex I. Implicated in several diseases, including MELAS syndrome; neurodegenerative disease (multiple); optic nerve disease (multiple); toxic shock syndrome; and type 2 diabetes mellitus. Biomarker of Alzheimer's disease; Parkinson's disease; and multiple sclerosis. [provided by Alliance of Genome Resources, Apr 2022]

TRNL1 (HGNC:7490): (mitochondrially encoded tRNA leucine 1 (UUA/G)) Implicated in cardiomyopathy. [provided by Alliance of Genome Resources, Apr 2022]

MT-RNR2 (HGNC:7471): (mitochondrially encoded 16S RNA) Enables G protein-coupled receptor binding activity; protein self-association; and receptor antagonist activity. Involved in several processes, including leukocyte chemotaxis; negative regulation of cell death; and negative regulation of neuroinflammatory response. Located in several cellular components, including mitochondrion; perinuclear region of cytoplasm; and sperm midpiece. [provided by Alliance of Genome Resources, Apr 2022]

MT-RNR2 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Apogee2 supports a benign effect, 0.10266045 < 0.5 .
• BP6: Variant M-3338-T-C is Benign according to our data. Variant chrM-3338-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 692338.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomadMitoHomoplasmic at 108

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ND1	unassigned_transcript_4789	c.32T>C	p.Val11Ala	missense_variant	Exon 1 of 1
TRNL1	unassigned_transcript_4788	c.*34T>C		downstream_gene_variant
RNR2	unassigned_transcript_4787	n.*109T>C		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-ND1	ENST00000361390.2	c.32T>C	p.Val11Ala	missense_variant	Exon 1 of 1	6		ENSP00000354687.2
MT-TL1	ENST00000386347.1	n.*34T>C		downstream_gene_variant		6
MT-RNR2	ENST00000387347.2	n.*109T>C		downstream_gene_variant		6

Frequencies

Mitomap GenBank AF: 0.0021 AC: 126

Gnomad homoplasmic AF: 0.0019 AC: 108 AN: 56427

Gnomad heteroplasmic AF: 0.000071 AC: 4 AN: 56427

Alfa AF: 0.00169 Hom.: 82

Mitomap

No disease associated.

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

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: Likely 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.3338T>C (YP_003024026.1:p.Val11Ala) variant in MTND1 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 -

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	0.10
Hmtvar	Benign	0.16
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.55	T
DEOGEN2	Benign	0.095	T
LIST_S2	Benign	0.29	T
MutationAssessor	Benign	-0.0050	N
PhyloP100		4.7
PROVEAN	Uncertain	-3.2	D
Sift4G	Benign	0.075	T
GERP RS		4.5
Varity_R		0.43

Other links and lift over

dbSNP: rs201969351; hg19: chrM-3339;