rs397515509

Variant names:

• chrM-4025-C-T
• rs397515509
• ENST00000361390.2:c.719C>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4 BP6_Very_Strong BS1 BS2

The ENST00000361390.2(MT-ND1):​c.719C>T​(p.Thr240Met) 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T240A) has been classified as Likely benign.

• Frequency: Mitomap GenBank: 𝑓 0.0069 (AC: 423)
• Consequence: MT-ND1 ENST00000361390.2 missense
• Scores: Apogee2 Benign 0.034
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1 No linked disesase in Mitomap
• Conservation: PhyloP100: -0.0950
• Publications: 16 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]

TRNI (HGNC:7488): (mitochondrially encoded tRNA isoleucine)

TRNI Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
• Leigh syndrome

  Inheritance: Mitochondrial Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP4: Apogee2 supports a benign effect, 0.033744924 < 0.5 .
• BP6: Variant M-4025-C-T is Benign according to our data. Variant chrM-4025-C-T is described in ClinVar as Benign. ClinVar VariationId is 65520.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: High frequency in mitomap database: 0.0069
• BS2: High AC in GnomadMitoHomoplasmic at 78

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ND1	unassigned_transcript_4789	c.719C>T	p.Thr240Met	missense_variant	Exon 1 of 1
TRNI	unassigned_transcript_4790	c.-238C>T		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-ND1	ENST00000361390.2	c.719C>T	p.Thr240Met	missense_variant	Exon 1 of 1	6		ENSP00000354687.2
MT-TI	ENST00000387365.1	n.-238C>T		upstream_gene_variant		6

Frequencies

Mitomap GenBank AF: 0.0069 AC: 423

Gnomad homoplasmic AF: 0.0014 AC: 78 AN: 56429

Gnomad heteroplasmic AF: 0.000053 AC: 3 AN: 56429

Alfa AF: 0.00149 Hom.: 99

Mitomap

No disease associated.

ClinVar

Significance: Benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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.4025C>T (YP_003024026.1:p.Thr240Met) 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: BA1 -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Leber optic atrophy Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Benign	0.034
Hmtvar	Benign	0.15
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.26	T
DEOGEN2	Benign	0.013	T
LIST_S2	Benign	0.82	T
MutationAssessor	Benign	-0.77	N
PhyloP100		-0.095
PROVEAN	Benign	1.9	N
GERP RS		-1.5
Varity_R		0.15

Other links and lift over

dbSNP: rs397515509; hg19: chrM-4026;