M-3316-G-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000361390.2(MT-ND1):​c.10G>C​(p.Ala4Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. 7/11 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A4T) has been classified as Benign.

• Frequency: Mitomap GenBank: 𝑓 0.0 (AC: 0)
• Consequence: MT-ND1 ENST00000361390.2 missense
• Scores: Apogee2 Uncertain 0.40
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 No linked disesase in Mitomap
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very low frequency in mitomap database: 0.0
• BP4: Apogee2 supports a benign effect, 0.40043953 < 0.5 .

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ND1	unassigned_transcript_4789	c.10G>C	p.Ala4Pro	missense_variant	Exon 1 of 1
TRNL1	unassigned_transcript_4788	c.*12G>C		downstream_gene_variant
RNR2	unassigned_transcript_4787	n.*87G>C		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-ND1	ENST00000361390.2	c.10G>C	p.Ala4Pro	missense_variant	Exon 1 of 1	6		ENSP00000354687.2
MT-TL1	ENST00000386347.1	n.*12G>C		downstream_gene_variant		6
MT-RNR2	ENST00000387347.2	n.*87G>C		downstream_gene_variant		6

Frequencies

Mitomap GenBank AF: 0.0 AC: 0

Gnomad homoplasmic AF: 0.000018 AC: 1 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

Leigh syndrome Uncertain:1

Oct 17, 2019

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NC_012920.1:m.3316G>C (YP_003024026.1:p.Ala4Pro) variant in MTND1 gene is interpretated to be a Uncertain Significance variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: BP4, PP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Uncertain	0.40
Hmtvar	Benign	0.32
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.33	T
DEOGEN2	Benign	0.063	T
LIST_S2	Pathogenic	0.97	D
MutationAssessor	Benign	1.6	L
PhyloP100		-0.23
PROVEAN	Benign	-1.6	N
Sift4G	Pathogenic	0.0010	D
GERP RS		-1.7
Varity_R		0.60

Other links and lift over

dbSNP: rs2853516; hg19: chrM-3317;