rs200145866

chrM-11253-T-C

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4 BP6_Moderate BS1 BS2

The ENST00000361381.2(MT-ND4):c.494T>C(p.Ile165Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 7/11 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Mitomap GenBank: 𝑓 0.0052 (AC: 319)
• Consequence: MT-ND4 ENST00000361381.2 missense
• Scores: Apogee2 Benign 0.078
• Clinical Significance: Benign criteria provided, single submitter B:1 O:1 LHON-PD
• Conservation: PhyloP100: 1.48

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 -11 ACMG points.

• BP4: Apogee2 supports a benign effect, 0.07761309 < 0.5 .
• BP6: Variant M-11253-T-C is Benign according to our data. Variant chrM-11253-T-C is described in ClinVar as [Benign]. Clinvar id is 65509.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: High frequency in mitomap database: 0.0052
• BS2: High AC in GnomadMitoHomoplasmic at 380

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.494T>C	p.Ile165Thr	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: 0.0052 AC: 319

Gnomad homoplasmic AF: 0.0067 AC: 380 AN: 56425

Gnomad heteroplasmic AF: 0.000053 AC: 3 AN: 56425

Alfa AF: 0.0108 Hom.: 421

Mitomap

LHON-PD

ClinVar

Significance: Benign

Submissions summary: Benign:1 Other: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.11253T>C (YP_003024035.1:p.Ile165Thr) 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

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Benign	0.078
Hmtvar	Benign	0.10
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.44	T
DEOGEN2	Benign	0.030	T
LIST_S2	Benign	0.30	T
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	8.7e-9	A
PROVEAN	Benign	-1.5	N
Sift	Benign	0.060	T
Sift4G	Benign	0.089	T
GERP RS		4.5
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: rs200145866; hg19: chrM-11254; COSMIC: COSV62294075; COSMIC: COSV62294075;