rs1599988

chrM-4216-T-C

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4 BP6_Moderate BA1

The ENST00000361390.2(MT-ND1):c.910T>C(p.Tyr304His) 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 (★).

• Frequency: Mitomap GenBank: 𝑓 0.10 (AC: 6406)
• Consequence: MT-ND1 ENST00000361390.2 missense
• Scores: Apogee2 Benign 0.19
• Clinical Significance: Benign criteria provided, single submitter P:1 U:1 B:1 O:1 LHON-/-Insulin-Resistance-/possible-adaptive-high-altitude-variant-/-miscarriage
• Conservation: PhyloP100: 0.217

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-TI (HGNC:7488): (mitochondrially encoded tRNA isoleucine)

TRNI (HGNC:):

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• BP4: Apogee2 supports a benign effect, 0.19259433 < 0.5 .
• BP6: Variant M-4216-T-C is Benign according to our data. Variant chrM-4216-T-C is described in ClinVar as [Benign]. Clinvar id is 9724.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: High frequency in mitomap database: 0.10479999

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRNI	TRNI.1			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MT-ND1	ENST00000361390.2	c.910T>C	p.Tyr304His	missense_variant	1/1			P1
MT-TI	ENST00000387365.1			upstream_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: 0.10 AC: 6406

Gnomad homoplasmic AF: 0.12 AC: 6570 AN: 55886

Gnomad heteroplasmic AF: 0.000054 AC: 3 AN: 55886

Alfa AF: 0.163 Hom.: 723

Mitomap

LHON-/-Insulin-Resistance-/possible-adaptive-high-altitude-variant-/-miscarriage

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Uncertain:1 Benign:1 Other: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.4216T>C (YP_003024026.1:p.Tyr304His) 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: BA1 -

not provided Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

-

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Benign	0.19
Hmtvar	Benign	0.11
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.60	T
DEOGEN2	Benign	0.011	T
LIST_S2	Benign	0.56	T
MutationAssessor	Benign	0.010	N
MutationTaster	Benign	1.0	N
PROVEAN	Benign	3.5	N
Sift4G	Benign	1.0	T
GERP RS		-6.8
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: rs1599988; hg19: chrM-4217; COSMIC: COSV62293824; COSMIC: COSV62293824;