M-10863-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4 BS2

The ENST00000361381.2(MT-ND4):c.104G>A(p.Ser35Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Mitomap GenBank: 𝑓 0.0 (AC: 3)
• Consequence: MT-ND4 ENST00000361381.2 missense
• Scores: Apogee2 Benign 0.20
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 No linked disesase in Mitomap
• Conservation: PhyloP100: 1.42

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very low frequency in mitomap database: 0.0
• BP4: Apogee2 supports a benign effect, 0.19844371 < 0.5 .
• BS2: High AC in GnomadMitoHomoplasmic at 5

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MT-ND4	ENST00000361381.2	c.104G>A	p.Ser35Asn	missense_variant	1/1			P1

Frequencies

GnomAD4 exome Cov.: 0

We have no GnomAD4 genomes data on this position. Probably position not covered by the project.

Mitomap GenBank AF: 0.0 AC: 3

Gnomad homoplasmic AF: 0.000089 AC: 5 AN: 56430

Gnomad heteroplasmic AF: 0.0 AC: 0 AN: 56430

Alfa AF: 0.000111 Hom.: 0

Mitomap

No disease associated.

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Leigh syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine

Oct 17, 2019

The NC_012920.1:m.10863G>A (YP_003024035.1:p.Ser35Asn) variant in MTND4 gene is interpretated to be a Uncertain Significance variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: no criteria -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Benign	0.20
Hmtvar	Pathogenic	0.76
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Benign	-0.24	T
DEOGEN2	Benign	0.035	T
LIST_S2	Benign	0.67	T
MutationAssessor	Uncertain	2.2	M
MutationTaster	Benign	1.0	N
PROVEAN	Benign	-2.0	N
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.061	T
GERP RS		-0.26
Varity_R		0.80

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1603222992; hg19: chrM-10864;