rs200873900

Variant names:

• chrM-11696-G-A
• rs200873900
• ENST00000361381.2:c.937G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4 BP6_Moderate BS1 BS2

The ENST00000361381.2(MT-ND4):​c.937G>A​(p.Val313Ile) 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 (★).

• Frequency: Mitomap GenBank: 𝑓 0.0060 (AC: 365)
• Consequence: MT-ND4 ENST00000361381.2 missense
• Scores: Apogee2 Benign 0.34
• Clinical Significance: Benign criteria provided, single submitter P:1 B:1 O:1 LHON-/-LDYT-/-DEAF-/-hypertension-helper-mut.
• Conservation: PhyloP100: 1.12
• Publications: 16 publications found

Genes affected

MT-ND4 (HGNC:7459): (mitochondrially encoded NADH dehydrogenase 4) Enables NADH dehydrogenase (ubiquinone) activity. Involved in mitochondrial electron transport, NADH to ubiquinone and mitochondrial respiratory chain complex I assembly. Part of mitochondrial respiratory chain complex I. Implicated in Leber hereditary optic neuropathy; Parkinson's disease; macular degeneration; and schizophrenia. Biomarker of Alzheimer's disease. [provided by Alliance of Genome Resources, Apr 2022]

MT-ND4 Gene-Disease associations (from GenCC):

• Leber hereditary optic neuropathy

  Inheritance: Mitochondrial Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• Leigh syndrome

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
• Leber plus disease

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet
• maternally-inherited Leigh syndrome

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet
• MELAS syndrome

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Apogee2 supports a benign effect, 0.33835188 < 0.5 .
• BP6: Variant M-11696-G-A is Benign according to our data. Variant chrM-11696-G-A is described in ClinVar as Benign. ClinVar VariationId is 9710.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: High frequency in mitomap database: 0.006
• BS2: High AC in GnomadMitoHomoplasmic at 56

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ND4	unassigned_transcript_4811	c.937G>A	p.Val313Ile	missense_variant	Exon 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-ND4	ENST00000361381.2	c.937G>A	p.Val313Ile	missense_variant	Exon 1 of 1	6		ENSP00000354961.2

Frequencies

Mitomap GenBank AF: 0.0060 AC: 365

Gnomad homoplasmic AF: 0.00099 AC: 56 AN: 56427

Gnomad heteroplasmic AF: 0.0 AC: 0 AN: 56427

Alfa AF: 0.00108 Hom.: 50

Mitomap

Disease(s): LHON-/-LDYT-/-DEAF-/-hypertension-helper-mut.

Status: Reported-/-possibly-synergistic

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Benign:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Leber optic atrophy and dystonia Pathogenic:1

Apr 22, 2003

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.11696G>A (YP_003024035.1:p.Val313Ile) variant in MTND4 gene is interpretated to be a Benign variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: BA1

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	0.34
Hmtvar	Benign	0.12
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.45	T
DEOGEN2	Benign	0.013	T
LIST_S2	Benign	0.29	T
MutationAssessor	Benign	-1.1	N
PhyloP100		1.1
PROVEAN	Benign	-0.32	N
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
GERP RS		0.49
Varity_R		0.13
Mutation Taster		=96/4	polymorphism

Other links and lift over

dbSNP: rs200873900; hg19: chrM-11697;