rs199476113

Positions:

• chrM-11084-A-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PS1_Moderate BP4 BP6_Moderate BS2

The ENST00000361381.2(MT-ND4):​c.325A>G​(p.Thr109Ala) 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 (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T109P) has been classified as Likely benign.

• Frequency: Mitomap GenBank: 𝑓 0.0037 (AC: 224)
• Consequence: MT-ND4 ENST00000361381.2 missense
• Scores: Apogee2 Benign 0.30
• Clinical Significance: Benign criteria provided, single submitter P:1 B:1 AD+-PD-MELAS
• Conservation: PhyloP100: 3.11

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 -5 ACMG points.

• PS1: Transcript ENST00000361381.2 (MT-ND4) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• BP4: Apogee2 supports a benign effect, 0.29805264 < 0.5 .
• BP6: Variant M-11084-A-G is Benign according to our data. Variant chrM-11084-A-G is described in ClinVar as [Benign]. Clinvar id is 9709.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomadMitoHomoplasmic at 94

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.325A>G	p.Thr109Ala	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: 0.0037 AC: 224

Gnomad homoplasmic AF: 0.0017 AC: 94 AN: 56432

Gnomad heteroplasmic AF: 0.000018 AC: 1 AN: 56432

Alfa AF: 0.000796 Hom.: 12

Mitomap

AD+-PD-MELAS

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Juvenile myopathy, encephalopathy, lactic acidosis AND stroke Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 1993

- -

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.11084A>G (YP_003024035.1:p.Thr109Ala) 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 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Benign	0.30
Hmtvar	Pathogenic	0.66
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.20	T
DEOGEN2	Benign	0.027	T
LIST_S2	Benign	0.66	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	5.4e-8	A
PROVEAN	Benign	-1.3	N
Sift	Pathogenic	0.0	D
Sift4G	Benign	1.0	T
GERP RS		3.3
Varity_R		0.39

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs199476113; hg19: chrM-11085;