M-3316-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4 BP6_Moderate BS1 BS2

The ENST00000361390.2(MT-ND1):c.10G>A(p.Ala4Thr) 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 benignin UniProt.

• Frequency: Mitomap GenBank: 𝑓 0.0094 (AC: 574)
• Consequence: MT-ND1 ENST00000361390.2 missense
• Scores: Apogee2 Benign 0.028
• Clinical Significance: Benign criteria provided, single submitter B:1 Diabetes-/-LHON-/-PEO-/-vascular-dementia
• Conservation: PhyloP100: -0.232

Genes affected

MT-ND1 (HGNC:7455): (mitochondrially encoded NADH dehydrogenase 1) Enables NADH dehydrogenase (ubiquinone) activity. Involved in mitochondrial electron transport, NADH to ubiquinone and mitochondrial respiratory chain complex I assembly. Located in mitochondrial membrane. Part of mitochondrial respiratory chain complex I. Implicated in several diseases, including MELAS syndrome; neurodegenerative disease (multiple); optic nerve disease (multiple); toxic shock syndrome; and type 2 diabetes mellitus. Biomarker of Alzheimer's disease; Parkinson's disease; and multiple sclerosis. [provided by Alliance of Genome Resources, Apr 2022]

MT-TL1 (HGNC:7490): (mitochondrially encoded tRNA leucine 1 (UUA/G)) Implicated in cardiomyopathy. [provided by Alliance of Genome Resources, Apr 2022]

TRNL1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• BP4: Apogee2 supports a benign effect, 0.02826732 < 0.5 .
• BP6: Variant M-3316-G-A is Benign according to our data. Variant chrM-3316-G-A is described in ClinVar as [Benign]. Clinvar id is 692333.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: High frequency in mitomap database: 0.0094
• BS2: High AC in GnomadMitoHomoplasmic at 258

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRNL1	TRNL1.1			downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MT-ND1	ENST00000361390.2	c.10G>A	p.Ala4Thr	missense_variant	1/1			P1
MT-TL1	ENST00000386347.1			downstream_gene_variant

Frequencies

GnomAD4 exome Cov.: 0

We have no GnomAD4 genomes data on this position. Probably position not covered by the project.

Mitomap GenBank AF: 0.0094 AC: 574

Gnomad homoplasmic AF: 0.0046 AC: 258 AN: 56400

Gnomad heteroplasmic AF: 0.00027 AC: 15 AN: 56400

Alfa AF: 0.00518 Hom.: 414

Mitomap

Diabetes-/-LHON-/-PEO-/-vascular-dementia

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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.3316G>A (YP_003024026.1:p.Ala4Thr) variant in MTND1 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	0.028
Hmtvar	Benign	0.090
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.44	T
DEOGEN2	Benign	0.0064	T
LIST_S2	Benign	0.77	T
MutationAssessor	Benign	-0.39	N
MutationTaster	Benign	1.0	N
PROVEAN	Benign	0.050	N
Sift4G	Benign	0.12	T
GERP RS		-1.7
Varity_R		0.15

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs2853516; hg19: chrM-3317;