rs1556422715

Variant names:

• chrM-3358-G-A
• rs1556422715
• ENST00000361390.2:c.52G>A

Variant summary

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

The ENST00000361390.2(MT-ND1):​c.52G>A​(p.Ala18Thr) variant causes a missense change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Mitomap GenBank: 𝑓 0.0 (AC: 3)
• Consequence: MT-ND1 ENST00000361390.2 missense
• Scores: Apogee2 Uncertain 0.47
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 No linked disesase in Mitomap
• Conservation: PhyloP100: 7.54
• Publications: 0 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, 0.4704494 < 0.5 .

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ND1	unassigned_transcript_4789	c.52G>A	p.Ala18Thr	missense_variant	Exon 1 of 1
TRNL1	unassigned_transcript_4788	c.*54G>A		downstream_gene_variant
RNR2	unassigned_transcript_4787	n.*129G>A		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-ND1	ENST00000361390.2	c.52G>A	p.Ala18Thr	missense_variant	Exon 1 of 1	6		ENSP00000354687.2
MT-TL1	ENST00000386347.1	n.*54G>A		downstream_gene_variant		6
MT-RNR2	ENST00000387347.2	n.*129G>A		downstream_gene_variant		6

Frequencies

Mitomap GenBank AF: 0.0 AC: 3

Gnomad homoplasmic AF: 0.000053 AC: 3 AN: 56426

Gnomad heteroplasmic AF: 0.000018 AC: 1 AN: 56426

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.3358G>A (YP_003024026.1:p.Ala18Thr) 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: BS1, PP4, PP6 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Uncertain	0.47
Hmtvar	Pathogenic	0.90
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Uncertain	0.087	D
DEOGEN2	Benign	0.14	T
LIST_S2	Benign	0.80	T
MutationAssessor	Pathogenic	3.3	M
PhyloP100		7.5
PROVEAN	Uncertain	-3.5	D
Sift4G	Uncertain	0.0080	D
GERP RS		4.5
Varity_R		0.86
Mutation Taster		=25/75	disease causing

Other links and lift over

dbSNP: rs1556422715; hg19: chrM-3359;