M-10914-G-A

Position:

• chrM-10914-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4 BP6_Moderate BS2

The ENST00000361381.2(MT-ND4):​c.155G>A​(p.Cys52Tyr) 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. C52R) has been classified as Uncertain significance.

• Frequency: Mitomap GenBank: 𝑓 0.00050 (AC: 33)
• Consequence: MT-ND4 ENST00000361381.2 missense
• Scores: Apogee2 Benign 0.026
• Clinical Significance: Benign criteria provided, single submitter B:1 No linked disesase in Mitomap
• Conservation: PhyloP100: -0.117

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 Benign. Variant got -7 ACMG points.

• BP4: Apogee2 supports a benign effect, 0.025794847 < 0.5 .
• BP6: Variant M-10914-G-A is Benign according to our data. Variant chrM-10914-G-A is described in ClinVar as [Benign]. Clinvar id is 693327.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomadMitoHomoplasmic at 9

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MT-ND4	ENST00000361381.2	c.155G>A	p.Cys52Tyr	missense_variant	1/1			ENSP00000354961	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: 0.00050 AC: 33

Gnomad homoplasmic AF: 0.00016 AC: 9 AN: 56411

Gnomad heteroplasmic AF: 0.000053 AC: 3 AN: 56411

Alfa AF: 0.000334 Hom.: 0

Mitomap

No disease associated.

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Leigh syndrome Benign:1

Benign, 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.10914G>A (YP_003024035.1:p.Cys52Tyr) 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: BS1, BS2, BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Benign	0.026
Hmtvar	Benign	0.10
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.45	T
DEOGEN2	Benign	0.0052	T
LIST_S2	Benign	0.53	T
MutationAssessor	Benign	-1.7	N
MutationTaster	Benign	1.0	N
PROVEAN	Benign	1.4	N
Sift	Benign	1.0	T
Sift4G	Benign	0.61	T
GERP RS		-1.3
Varity_R		0.14

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs878931758; hg19: chrM-10915; COSMIC: COSV62293897; COSMIC: COSV62293897;