M-3388-C-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 id is 29998.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomadMitoHomoplasmic at 42

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ND1	unassigned_transcript_4789	c.82C>A	p.Leu28Met	missense_variant	Exon 1 of 1
TRNL1	unassigned_transcript_4788	c.*84C>A		downstream_gene_variant
RNR2	unassigned_transcript_4787	n.*159C>A		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-ND1	ENST00000361390.2	c.82C>A	p.Leu28Met	missense_variant	Exon 1 of 1	6		ENSP00000354687.2
MT-TL1	ENST00000386347.1	n.*84C>A		downstream_gene_variant		6
MT-RNR2	ENST00000387347.2	n.*159C>A		downstream_gene_variant		6

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 v4.3

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;