chrM-10931-T-C

Position:

• chrM-10931-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4 BP6 BS2

The ENST00000361381.2(MT-ND4):​c.172T>C​(p.Ser58Pro) 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Mitomap GenBank: 𝑓 0.00010 (AC: 8)
• Consequence: MT-ND4 ENST00000361381.2 missense
• Scores: Apogee2 Benign 0.29
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1 No linked disesase in Mitomap
• Conservation: PhyloP100: 0.0340

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 -6 ACMG points.

• BP4: Apogee2 supports a benign effect, 0.29081905 < 0.5 .
• BP6: Variant M-10931-T-C is Benign according to our data. Variant chrM-10931-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 618728.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS2: High AC in GnomadMitoHomoplasmic at 119

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.172T>C	p.Ser58Pro	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: 0.00010 AC: 8

Gnomad homoplasmic AF: 0.0021 AC: 119 AN: 56428

Gnomad heteroplasmic AF: 0.000053 AC: 3 AN: 56428

Mitomap

No disease associated.

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

May 26, 2018

The m.10931T>C variant affects the mitochondrially-encoded MT-ND4 gene. Although the m.10931T>C variant is rare in the general population (identified in six individuals in the MITOMAP database), it has not been reported in association with a mitochondrial disorder and affects a weakly conserved amino acid (Alamut software v2.11.0). Therefore, due to limited information, the clinical significance of the m.10931T>C variant is uncertain at this time. -

Leigh syndrome Benign:1

Likely 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.10931T>C (YP_003024035.1:p.Ser58Pro) variant in MTND4 gene is interpretated to be a Likely Benign variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: BS4, BP4, BP6 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Benign	0.29
Hmtvar	Pathogenic	0.75
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Benign	-0.36	T
DEOGEN2	Benign	0.066	T
LIST_S2	Benign	0.54	T
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	1.0	N
PROVEAN	Uncertain	-2.6	D
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.0080	D
GERP RS		-3.1
Varity_R		0.90

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1569484408; hg19: chrM-10932;