chrM-7444-G-A
Position:
Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM4BP6_Very_StrongBS2
The ENST00000361624.2(MT-CO1):c.1541G>A(p.Ter514LysextTer?) variant causes a stop lost change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★).
Frequency
Mitomap GenBank:
𝑓 0.0035 ( AC: 213 )
Consequence
MT-CO1
ENST00000361624.2 stop_lost
ENST00000361624.2 stop_lost
Scores
Clinical Significance
LHON-/-SNHL-/-DEAF-modulator
Conservation
PhyloP100: 1.42
Genes affected
MT-CO1 (HGNC:7419): (mitochondrially encoded cytochrome c oxidase I) Contributes to cytochrome-c oxidase activity. Predicted to be involved in electron transport coupled proton transport and mitochondrial electron transport, cytochrome c to oxygen. Part of mitochondrial respiratory chain complex III and mitochondrial respiratory chain complex IV. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -10 ACMG points.
PM4
Stoplost variant in ENST00000361624.2 Downstream stopcodon found after 5 codons.
BP6
Variant M-7444-G-A is Benign according to our data. Variant chrM-7444-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 9663.Status of the report is reviewed_by_expert_panel, 3 stars.
BS2
High AC in GnomadMitoHomoplasmic at 302
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COX1 | COX1.1 use as main transcript | c.1541G>A | p.Ter514LysextTer? | stop_lost | 1/1 | ||
TRNS1 | TRNS1.1 use as main transcript | downstream_gene_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MT-CO1 | ENST00000361624.2 | c.1541G>A | p.Ter514LysextTer? | stop_lost | 1/1 | P1 | |||
MT-TS1 | ENST00000387416.2 | downstream_gene_variant |
Frequencies
GnomAD4 exome Cov.: 0
GnomAD4 exome
Cov.:
0
We have no GnomAD4 genomes data on this position. Probably position not covered by the project.
Mitomap GenBank
AF:
AC:
213
Gnomad homoplasmic
AF:
AC:
302
AN:
56419
Gnomad heteroplasmic
AF:
AC:
10
AN:
56419
Alfa
AF:
Hom.:
Mitomap
LHON-/-SNHL-/-DEAF-modulator
ClinVar
Significance: Likely benign
Submissions summary: Pathogenic:4Benign:2Other:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Mitochondrial non-syndromic sensorineural hearing loss Pathogenic:1Other:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 2005 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Aminoglycoside-induced deafness Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 14, 2007 | - - |
Leber optic atrophy Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 2005 | - - |
Mitochondrial disease Benign:1
Likely benign, reviewed by expert panel | curation | ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen | Jun 26, 2023 | The m.7444G>A (p.term514K) in MT-CO1 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel on June 26, 2023. This variant has been reported in several individuals with features of primary mitochondrial disease beginning in 1992 (Leber Hereditary Optic Neuropathy or LHON, PMID: 1322638; hearing loss, PMID: 16500624), however other genetic etiologies were not excluded due to technical limitations at the time and this variant is now recognized to be present at high frequencies in population databases. Furthermore, this variant has been seen in individuals with other well-known pathogenic mitochondrial DNA variants (family with LHON and m.3460G>A, PMID: 7901141; family with hearing loss and m.1555A>G, PMID: 16152638; BP2). The variant was seen at homoplasmy in affected and unaffected family members in several of these publications precluding consideration of segregation evidence. There are no reported de novo occurrences of this variant to our knowledge. Some functional characterization was performed in patient cells, however abnormalities noted were nonspecific and other genetic etiologies were not assessed (PMID: 1322638). This variant is present at considerable frequencies in population databases (BS1). The frequency in the MITOMAP GenBank sequences is 206/59,389 (0.347%; 12/12 individuals in Hg V7, 3/3 individuals in Hg H40b, 4/4 individuals in V7b, 4/4 individuals in W4b, 84/86 individuals in V7a, also seen in individuals from M22b, M38a, H11, HV20, P2, B2e, and others). The frequency in gnomAD v3.1.2 is 302/56,419 (0.535%). Indeed, there are 302 homoplasmic occurrences (seen in all populations except Amish and Middle Eastern, seen across every haplogroup listed; seen in individuals ages 30 years to >80 years) in addition to 10 heteroplasmic occurrences (seen in multiple populations, haplogroups, and heteroplasmy levels). The frequency in the Helix dataset is 775/195,983 (0.395%). Indeed, there are 775 homoplasmic occurrences (seen across many haplogroups) and 24 heteroplasmic occurrences (seen across many haplogroups). There are no in silico predictors for this type of variant in mitochondrial DNA. In summary, this variant meets criteria to be classified as likely benign 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 June 26, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied: BS1, BP2. - |
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.7444G>A (YP_003024028.1:p.Ter514LysextX4) variant in MTCO1 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:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
T
MutationTaster
Benign
A
GERP RS
Varity_R
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at