ENST00000361390.2:c.82C>A

Variant names:

• chrM-3388-C-A
• rs387906730
• ENST00000361390.2:c.82C>A

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.82C>A​(p.Leu28Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 7/11 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Mitomap GenBank: 𝑓 0.00050 (AC: 30)
• Consequence: MT-ND1 ENST00000361390.2 missense
• Scores: Apogee2 Benign 0.39
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 U:1 B:2 Materally-Inherited-Nonsyndromic-Deafness
• Conservation: PhyloP100: -2.21
• 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, 0.39391762 < 0.5 .
• BP6: Variant M-3388-C-A is Benign according to our data. Variant chrM-3388-C-A is described in ClinVar as Benign. ClinVar VariationId is 29998.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomadMitoHomoplasmic at 42

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000361390.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT-ND1	ENST00000361390.2	TSL:6	c.82C>A	p.Leu28Met	missense	Exon 1 of 1	ENSP00000354687.2
	MT-TL1	ENST00000386347.1	TSL:6	n.*84C>A		downstream_gene	N/A
	MT-RNR2	ENST00000387347.2	TSL:6	n.*159C>A		downstream_gene	N/A

Frequencies

Mitomap GenBank AF: 0.00050 AC: 30

Gnomad homoplasmic AF: 0.00074 AC: 42 AN: 56434

Gnomad heteroplasmic AF: 0.0 AC: 0 AN: 56434

Alfa AF: 0.000618 Hom.: 10

Mitomap

Disease(s): Materally-Inherited-Nonsyndromic-Deafness

Status: Reported

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Uncertain:1 Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mitochondrial non-syndromic sensorineural hearing loss Pathogenic:1

Apr 01, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Optic atrophy Uncertain:1

Jan 01, 2010

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance: Uncertain significance

Review Status: no assertion criteria provided

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.3388C>A (YP_003024026.1:p.Leu28Met) 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, BS4

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Apogee2	Benign	0.39
Hmtvar	Pathogenic	0.81
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.0048	T
DEOGEN2	Benign	0.041	T
LIST_S2	Uncertain	0.91	D
MutationAssessor	Benign	1.6	L
PhyloP100		-2.2
PROVEAN	Benign	-1.7	N
GERP RS		-9.1
Varity_R		0.56
Mutation Taster		=48/52	disease causing

Other links and lift over

dbSNP: rs387906730; hg19: chrM-3389;