M-10644-G-A

Position:

• chrM-10644-G-A

Variant summary

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

The ENST00000361335.1(MT-ND4L):​c.175G>A​(p.Val59Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 7/10 in silico tools predict 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-ND4L ENST00000361335.1 missense
• Scores: Apogee2 Benign 0.012
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1 No linked disesase in Mitomap
• Conservation: PhyloP100: -0.793

Genes affected

MT-ND4L (HGNC:7460): (mitochondrially encoded NADH 4L dehydrogenase) Predicted to enable NADH dehydrogenase (ubiquinone) activity. Predicted to be located in mitochondrial inner membrane. Implicated in Leber hereditary optic neuropathy and diabetes mellitus. [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, 0.011528987 < 0.5 .
• BP6: Variant M-10644-G-A is Benign according to our data. Variant chrM-10644-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 618217.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS2: High AC in GnomadMitoHomoplasmic at 14

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MT-ND4L	ENST00000361335.1	c.175G>A	p.Val59Met	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: 0.00025 AC: 14 AN: 56428

Gnomad heteroplasmic AF: 0.000018 AC: 1 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 18, 2018

The m.10644G>A variant affects the sequence of the MT-ND4L gene (c.175G>A; p.Val59Met), and has not been associated with disease in published literature. This variant is rare in the MITOMAP population database with an overall frequency of 0.01%. Based on the available information, the clinical significance of this variant cannot be determined with certainty. -

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.10644G>A (YP_003024034.1:p.Val59Met) variant in MTND4L gene is interpretated to be a Likely Benign variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: BS1, BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Benign	0.012
Hmtvar	Benign	0.080
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.46	T
DEOGEN2	Benign	0.0088	T
LIST_S2	Benign	0.56	T
MutationTaster	Benign	1.0	N
PROVEAN	Benign	0.21	N
Sift	Benign	1.0	T
Sift4G	Benign	0.69	T
GERP RS		-8.2
Varity_R		0.082

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1569484385; hg19: chrM-10645;