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

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000361390.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT-ND1	ENST00000361390.2	TSL:6	c.910T>C	p.Tyr304His	missense	Exon 1 of 1	ENSP00000354687.2	P03886
	MT-TI	ENST00000387365.1	TSL:6	n.-47T>C		upstream_gene	N/A
	MT-TM	ENST00000387377.1	TSL:6	n.-186T>C		upstream_gene	N/A

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	1	-	Leber optic atrophy (2)
-	-	1	Leigh syndrome (1)
-	-	1	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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;