rs199476113

Variant names:

• chrM-11084-A-G
• rs199476113
• ENST00000361381.2:c.325A>G
• MT-ND4 p.Thr109Ala

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. 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 (★).

• 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
• Publications: 12 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 -7 ACMG points.

• 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 VariationId is 9709.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomadMitoHomoplasmic at 94

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000361381.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT-ND4	ENST00000361381.2	TSL:6	c.325A>G	p.Thr109Ala	missense	Exon 1 of 1	ENSP00000354961.2	P03905

Frequencies

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: 0.000633 Hom.: 16

Mitomap

Disease(s): AD+-PD-MELAS

Status: Conflicting-reports

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Leigh syndrome (1)
1	-	-	MELAS syndrome (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		3.1
PROVEAN	Benign	-1.3	N
Sift	Pathogenic	0.0	D
Sift4G	Benign	1.0	T
Varity_R		0.39
Mutation Taster		=43/157	disease causing

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs199476113;

hg19: chrM-11085;