M-3316-G-A

Variant names:

• chrM-3316-G-A
• rs2853516
• ENST00000361390.2:c.10G>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4 BP6_Very_Strong BS1 BS2

The ENST00000361390.2(MT-ND1):​c.10G>A​(p.Ala4Thr) 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A4P) has been classified as Uncertain significance.

• Frequency: Mitomap GenBank: 𝑓 0.0094 (AC: 574)
• Consequence: MT-ND1 ENST00000361390.2 missense
• Scores: Apogee2 Benign 0.028
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3 Diabetes-/-LHON-/-PEO-/-vascular-dementia
• Conservation: PhyloP100: -0.232
• Publications: 17 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 -17 ACMG points.

• BP4: Apogee2 supports a benign effect, 0.02826732 < 0.5 .
• BP6: Variant M-3316-G-A is Benign according to our data. Variant chrM-3316-G-A is described in ClinVar as [Benign]. Clinvar id is 692333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: High frequency in mitomap database: 0.0094
• BS2: High AC in GnomadMitoHomoplasmic at 258

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ND1	unassigned_transcript_4789	c.10G>A	p.Ala4Thr	missense_variant	Exon 1 of 1
TRNL1	unassigned_transcript_4788	c.*12G>A		downstream_gene_variant
RNR2	unassigned_transcript_4787	n.*87G>A		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-ND1	ENST00000361390.2	c.10G>A	p.Ala4Thr	missense_variant	Exon 1 of 1	6		ENSP00000354687.2
MT-TL1	ENST00000386347.1	n.*12G>A		downstream_gene_variant		6
MT-RNR2	ENST00000387347.2	n.*87G>A		downstream_gene_variant		6

Frequencies

Mitomap GenBank AF: 0.0094 AC: 574

Gnomad homoplasmic AF: 0.0046 AC: 258 AN: 56400

Gnomad heteroplasmic AF: 0.00027 AC: 15 AN: 56400

Alfa AF: 0.00498 Hom.: 472

Mitomap

Disease(s): Diabetes-/-LHON-/-PEO-/-vascular-dementia

Status: Reported|-hg-D1-D2-M33-R30-marker

ClinVar

Significance: 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: 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.3316G>A (YP_003024026.1:p.Ala4Thr) 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 -

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	0.028
Hmtvar	Benign	0.090
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.44	T
DEOGEN2	Benign	0.0064	T
LIST_S2	Benign	0.77	T
MutationAssessor	Benign	-0.39	N
PhyloP100		-0.23
PROVEAN	Benign	0.050	N
Sift4G	Benign	0.12	T
GERP RS		-1.7
Varity_R		0.15
Mutation Taster		=95/5	polymorphism

Other links and lift over

dbSNP: rs2853516; hg19: chrM-3317;