NM_002693.3:c.1433+1G>C
Variant summary
Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_ModeratePM2PP5_Moderate
The NM_002693.3(POLG):c.1433+1G>C variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Consequence
NM_002693.3 splice_donor, intron
Scores
Clinical Significance
Conservation
Publications
- progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
- mitochondrial DNA depletion syndrome 4aInheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Orphanet, G2P
- sensory ataxic neuropathy, dysarthria, and ophthalmoparesisInheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, G2P
- autosomal dominant progressive external ophthalmoplegiaInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- autosomal recessive progressive external ophthalmoplegiaInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- mitochondrial neurogastrointestinal encephalomyopathyInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- recessive mitochondrial ataxia syndromeInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- spinocerebellar ataxia with epilepsyInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- Leigh syndromeInheritance: AR Classification: LIMITED Submitted by: ClinGen
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ACMG classification
Our verdict: Likely_pathogenic. The variant received 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
POLG | NM_002693.3 | c.1433+1G>C | splice_donor_variant, intron_variant | Intron 7 of 22 | ENST00000268124.11 | NP_002684.1 | ||
POLG | NM_001126131.2 | c.1433+1G>C | splice_donor_variant, intron_variant | Intron 7 of 22 | NP_001119603.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 34
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Progressive sclerosing poliodystrophy Pathogenic:1
This sequence change affects a donor splice site in intron 7 of the POLG gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in POLG are known to be pathogenic (PMID: 18546365). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with Alpers syndrome (PMID: 21880868; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at