rs199474674

Variant names:

• chrM-5532-G-A
• rs199474674
• unassigned_transcript_4794:c.21G>A

Your query was ambiguous. Multiple possible variants found:

• chrM-5532-G-A
• chrM-5532-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Mitomap GenBank: 𝑓 0.0 (AC: 1)
• Consequence: TRNW synonymous
• Scores: Mitotip Benign 7.4
• Clinical Significance: Uncertain significance reviewed by expert panel P:2 U:1 Gastrointestinal-Syndrome
• Conservation: PhyloP100: 4.17

Genes affected

TRNW (HGNC:7501): (mitochondrially encoded tRNA tryptophan)

ND2 (HGNC:7456): (mitochondrially encoded NADH dehydrogenase 2) 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; multiple sclerosis; myocardial infarction; neurodegenerative disease (multiple); and urinary bladder cancer. [provided by Alliance of Genome Resources, Apr 2022]

TRNN (HGNC:7493): (mitochondrially encoded tRNA asparagine)

TRNA (HGNC:7475): (mitochondrially encoded tRNA alanine)

TRNC (HGNC:7477): (mitochondrially encoded tRNA cysteine)

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very low frequency in mitomap database: 0.0
• PP5: Variant M-5532-G-A is Pathogenic according to our data. Variant chrM-5532-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 9557.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRNW	unassigned_transcript_4794	c.21G>A	p.Gln7Gln	synonymous_variant	Exon 1 of 1
ND2	unassigned_transcript_4793	c.*21G>A		downstream_gene_variant
TRNN	unassigned_transcript_4796	c.*125C>T		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt

Frequencies

GnomAD4 exome Cov.: 0

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

Mitomap GenBank AF: 0.0 AC: 1

Mitomap

Gastrointestinal-Syndrome

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

MELAS syndrome Pathogenic:1

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neurogastrointestinal syndrome, mitochondrial Pathogenic:1

Jun 01, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mitochondrial disease Uncertain:1

May 13, 2024

ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The m.5532G>A variant in MT-TW has been reported in one individual with primary mitochondrial disease to date (PMID: 15054399), in a 16-year-old girl with failure to thrive, short stature, recurrent vomiting, developmental delay and regression, ophthalmoplegia, ptosis, pigmentary retinopathy, sensorineural hearing loss, and myopathy. Brain imaging showed generalized atrophy and periventricular white matter changes. Elevated lactate was seen in blood and cerebrospinal fluid. Muscle biopsy showed ragged red fibers and mitochondrial respiratory chain complex I and IV deficiency. The variant was present at 92% heteroplasmy in muscle, 37% in fibroblasts, and 21% in blood. The variant was present at lower heteroplasmy levels in blood from her healthy mother (7%) and brother (9%; PP1; PMID: 15054399). There are no other individuals or families reported in the medical literature. Although there is one occurrence of this variant in population databases (1/61,134 in MITOMAP, absent in Helix and gnomad v3.1.2), the frequency is still low (PM2_supporting). In silico predictors are conflicting as the computational predictor MitoTIP suggests this variant is likely benign (19.4 percentile) but HmtVAR predicts it to be deleterious with a score of 0.7. Single fiber testing showed higher levels of the variant in COX-negative fibers (>90%) than in COX-positive fibers (6-85%, p<0.0001, PS3_supporting, PMID: 15054399). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on May 13, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PP1, PS3_supporting, PM2_supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Benign	7.4
Hmtvar	Pathogenic	0.70

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs199474674; hg19: chrM-5533;