rs199476120

Variant names:

• chrM-3397-A-G
• rs199476120
• ENST00000361390.2:c.91A>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 1P and 6B. PP3 BP6_Moderate BS2

The ENST00000361390.2(MT-ND1):​c.91A>G​(p.Met31Val) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic 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. M31I) has been classified as Benign.

• Frequency: Mitomap GenBank: 𝑓 0.0027 (AC: 168)
• Consequence: MT-ND1 ENST00000361390.2 missense
• Scores: Apogee2 Pathogenic 0.69
• Clinical Significance: Benign criteria provided, single submitter P:2 B:1 ADPD-/-possibly-LVNC-cardiomyopathy-associated-/-resistance-to-high-altitude-pulmonary-edema
• Conservation: PhyloP100: 8.73
• Publications: 24 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: Likely_benign. The variant received -5 ACMG points.

• PP3: Apogee2 supports a deletorius effect, 0.68593884 >= 0.5 .
• BP6: Variant M-3397-A-G is Benign according to our data. Variant chrM-3397-A-G is described in ClinVar as Benign. ClinVar VariationId is 9726.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomadMitoHomoplasmic at 85

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ND1	unassigned_transcript_4789	c.91A>G	p.Met31Val	missense_variant	Exon 1 of 1
TRNL1	unassigned_transcript_4788	c.*93A>G		downstream_gene_variant
RNR2	unassigned_transcript_4787	n.*168A>G		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-ND1	ENST00000361390.2	c.91A>G	p.Met31Val	missense_variant	Exon 1 of 1	6		ENSP00000354687.2
MT-TL1	ENST00000386347.1	n.*93A>G		downstream_gene_variant		6
MT-RNR2	ENST00000387347.2	n.*168A>G		downstream_gene_variant		6

Frequencies

Mitomap GenBank AF: 0.0027 AC: 168

Gnomad homoplasmic AF: 0.0015 AC: 85 AN: 56427

Gnomad heteroplasmic AF: 0.000018 AC: 1 AN: 56427

Alfa AF: 0.00189 Hom.: 8

Mitomap

Disease(s): ADPD-/-possibly-LVNC-cardiomyopathy-associated-/-resistance-to-high-altitude-pulmonary-edema

Status: Reported

ClinVar

Significance: Benign

Submissions summary: Pathogenic:2 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Parkinson disease, late-onset Pathogenic:1

Jul 01, 1993

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Alzheimer disease Pathogenic:1

Jul 01, 1993

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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.3397A>G (YP_003024026.1:p.Met31Val) 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 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.69
Hmtvar	Pathogenic	0.42
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.50	T
PhyloP100		8.7
GERP RS		4.5
Varity_R		0.75
Mutation Taster		=54/146	disease causing

Other links and lift over

dbSNP: rs199476120; hg19: chrM-3398;