rs28359178

Positions:

• chrM-13708-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 2P and 11B. PS1_Moderate BP4 BP6_Moderate BA1

The ENST00000361567.2(MT-ND5):​c.1372G>A​(p.Ala458Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 8/11 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.

• Frequency: Mitomap GenBank: 𝑓 0.075 (AC: 4560)
• Consequence: MT-ND5 ENST00000361567.2 missense
• Scores: Apogee2 Benign 0.31
• Clinical Significance: Benign criteria provided, single submitter P:1 U:1 B:1 LHON-/-Increased-MS-risk-/-higher-freq-in-PD-ADS
• Conservation: PhyloP100: 0.633

Genes affected

MT-ND5 (HGNC:7461): (mitochondrially encoded NADH dehydrogenase 5) 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; Leigh disease; and MELAS syndrome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• PS1: Transcript ENST00000361567.2 (MT-ND5) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• BP4: Apogee2 supports a benign effect, 0.30702576 < 0.5 .
• BP6: Variant M-13708-G-A is Benign according to our data. Variant chrM-13708-G-A is described in ClinVar as [Benign]. Clinvar id is 9696.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: High frequency in mitomap database: 0.0746

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MT-ND5	ENST00000361567.2	c.1372G>A	p.Ala458Thr	missense_variant	1/1			ENSP00000354813	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: 0.075 AC: 4560

Gnomad homoplasmic AF: 0.076 AC: 4263 AN: 56361

Gnomad heteroplasmic AF: 0.00037 AC: 21 AN: 56361

Alfa AF: 0.114 Hom.: 2906

Mitomap

LHON-/-Increased-MS-risk-/-higher-freq-in-PD-ADS

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Uncertain:1 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Leber optic atrophy Pathogenic:1 Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 30, 1992	- -
Uncertain significance, no assertion criteria provided	curation	GeneReviews	Sep 19, 2013	- -

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.13708G>A (YP_003024036.1:p.Ala458Thr) variant in MTND5 gene is interpretated to be a Benign variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: BA1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Benign	0.31
Hmtvar	Benign	0.21
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.41	T
DEOGEN2	Benign	0.030	T
LIST_S2	Benign	0.58	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	1.0	N
PROVEAN	Benign	-1.5	N
Sift4G	Benign	0.078	T
GERP RS		-5.7
Varity_R		0.29

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs28359178; hg19: chrM-13709;