rs199476127

Positions:

• chrM-6721-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★).

• Frequency: Mitomap GenBank: Absent
• Consequence: COX1 missense
• Scores: Apogee2 Pathogenic 0.83
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:1 Acquired-Idiopathic-Sideroblastic-Anemia
• Conservation: PhyloP100: 4.02

Genes affected

COX1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: No frequency data in Mitomap. Probably very rare.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COX1	unassigned_transcript_4800	c.818T>C	p.Met273Thr	missense_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	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

Acquired-Idiopathic-Sideroblastic-Anemia

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Myelodysplastic syndrome with ring sideroblasts Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 15, 1997

- -

Mitochondrial disease Uncertain:1

Uncertain significance, reviewed by expert panel

curation

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

Mar 11, 2024

The m.6721T>C (p.M273T) variant in MT-CO1 has been reported in one individual to date, in a 58-year-old woman with acquired idiopathic sideroblastic anemia (PMID: 9389715). The variant was present in bone marrow from the proband and absent in her mother’s blood (PM6_supporting). There have not been additional affected individuals reported to date. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.72 (Min=0, Max=1; APOGEE2 score is 0.834), which predicts a damaging effect on gene function (PP3). There are no cybrids, single fiber studies, or other functional assays reported on this variant. 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 March 11, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PP3, PM2_supporting, PM6_supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.83
Hmtvar	Pathogenic	0.85
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Benign	-0.14	T
DEOGEN2	Benign	0.22	T
LIST_S2	Benign	0.81	T
MutationAssessor	Pathogenic	4.7	H
PROVEAN	Uncertain	-4.4	D
Sift4G	Pathogenic	0.0	D
GERP RS		5.3
Varity_R		0.66

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs199476127; hg19: chrM-6722;