ENST00000361390.2:c.4C>T

Variant names:

• chrM-3310-C-T
• rs1603218889
• ENST00000361390.2:c.4C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The ENST00000361390.2(MT-ND1):​c.4C>T​(p.Pro2Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 8/11 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Mitomap GenBank: 𝑓 0.00020 (AC: 13)
• Consequence: MT-ND1 ENST00000361390.2 missense
• Scores: Apogee2 Benign 0.019
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 Diabetes-/-HCM
• Conservation: PhyloP100: -2.21
• 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Apogee2 supports a benign effect, 0.019101202 < 0.5 .
• BS2: High AC in GnomadMitoHomoplasmic at 6

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ND1	unassigned_transcript_4789	c.4C>T	p.Pro2Ser	missense_variant	Exon 1 of 1
TRNL1	unassigned_transcript_4788	c.*6C>T		downstream_gene_variant
RNR2	unassigned_transcript_4787	n.*81C>T		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-ND1	ENST00000361390.2	c.4C>T	p.Pro2Ser	missense_variant	Exon 1 of 1	6		ENSP00000354687.2
MT-TL1	ENST00000386347.1	n.*6C>T		downstream_gene_variant		6
MT-RNR2	ENST00000387347.2	n.*81C>T		downstream_gene_variant		6

Frequencies

Mitomap GenBank AF: 0.00020 AC: 13

Gnomad homoplasmic AF: 0.00011 AC: 6 AN: 56430

Gnomad heteroplasmic AF: 0.000018 AC: 1 AN: 56430

Mitomap

Disease(s): Diabetes-/-HCM

Status: Reported

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.3310C>T (YP_003024026.1:p.Pro2Ser) 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: PM10, BS1, BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Benign	0.019
Hmtvar	Benign	0.15
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.22	T
DEOGEN2	Benign	0.0014	T
LIST_S2	Pathogenic	1.0	D
MutationAssessor	Benign	-0.97	N
PhyloP100		-2.2
PROVEAN	Benign	0.74	N
Sift4G	Benign	0.34	T
GERP RS		-2.4
Varity_R		0.14
Mutation Taster		=95/5	polymorphism

Other links and lift over

dbSNP: rs1603218889; hg19: chrM-3311;