rs1599988

Variant names:

• chrM-4216-T-C
• rs1599988
• ENST00000361390.2:c.910T>C

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4 BP6_Very_Strong 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 (★★). Synonymous variant affecting the same amino acid position (i.e. Y304Y) has been classified as Likely 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, multiple submitters, no conflicts P:1 U:1 B:3 O:1 LHON-/-Insulin-Resistance-/possible-adaptive-high-altitude-variant-/-miscarriage
• Conservation: PhyloP100: 0.217
• Publications: 91 publications found

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]

TRNI (HGNC:7488): (mitochondrially encoded tRNA isoleucine)

TRNM (HGNC:7492): (mitochondrially encoded tRNA methionine)

TRNQ (HGNC:7495): (mitochondrially encoded tRNA glutamine)

TRNQ Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -17 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 VariationId is 9724.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: High frequency in mitomap database: 0.10479999

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ND1	unassigned_transcript_4789	c.910T>C	p.Tyr304His	missense_variant	Exon 1 of 1
TRNI	unassigned_transcript_4790	c.-47T>C		upstream_gene_variant
TRNM	unassigned_transcript_4792	c.-186T>C		upstream_gene_variant
TRNQ	unassigned_transcript_4791	c.*113A>G		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-ND1	ENST00000361390.2	c.910T>C	p.Tyr304His	missense_variant	Exon 1 of 1	6		ENSP00000354687.2
MT-TI	ENST00000387365.1	n.-47T>C		upstream_gene_variant		6
MT-TM	ENST00000387377.1	n.-186T>C		upstream_gene_variant		6
MT-TQ	ENST00000387372.1	n.*113A>G		downstream_gene_variant		6

Frequencies

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

Disease(s): LHON-/-Insulin-Resistance-/possible-adaptive-high-altitude-variant-/-miscarriage

Status: Conflicting-reports

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Uncertain:1 Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Leber optic atrophy Pathogenic:1 Uncertain:1

Sep 30, 1992

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Sep 19, 2013

GeneReviews

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: curation

- -

not provided Benign:1 Other:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

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. -

not specified Benign:1

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Leigh syndrome Benign:1

Oct 17, 2019

Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

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
PhyloP100		0.22
PROVEAN	Benign	3.5	N
Sift4G	Benign	1.0	T
GERP RS		-6.8
Varity_R		0.15
Mutation Taster		=82/18	polymorphism

Other links and lift over

dbSNP: rs1599988; hg19: chrM-4217; COSMIC: COSV62293824; COSMIC: COSV62293824;