9-127843248-G-C
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3PP5_Moderate
The NM_001114753.3(ENG):c.68-3C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign 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_001114753.3 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ENG | NM_001114753.3 | c.68-3C>G | splice_region_variant, intron_variant | Intron 1 of 14 | ENST00000373203.9 | NP_001108225.1 | ||
ENG | NM_000118.4 | c.68-3C>G | splice_region_variant, intron_variant | Intron 1 of 13 | NP_000109.1 | |||
ENG | NM_001278138.2 | c.-479-3C>G | splice_region_variant, intron_variant | Intron 1 of 14 | NP_001265067.1 | |||
ENG | NM_001406715.1 | c.68-3C>G | splice_region_variant, intron_variant | Intron 1 of 7 | NP_001393644.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ENG | ENST00000373203.9 | c.68-3C>G | splice_region_variant, intron_variant | Intron 1 of 14 | 1 | NM_001114753.3 | ENSP00000362299.4 | |||
ENG | ENST00000344849.4 | c.68-3C>G | splice_region_variant, intron_variant | Intron 1 of 13 | 1 | ENSP00000341917.3 | ||||
ENG | ENST00000480266.6 | c.-479-3C>G | splice_region_variant, intron_variant | Intron 1 of 14 | 2 | ENSP00000479015.1 |
Frequencies
GnomAD3 genomes Cov.: 30
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 30
ClinVar
Submissions by phenotype
Hereditary hemorrhagic telangiectasia Pathogenic:1
For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with altered splicing resulting in skipping of exon 2 (PMID: 25970827). ClinVar contains an entry for this variant (Variation ID: 568333). This variant has been observed in individuals with ENG-related disease (PMID: 25970827; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 1 of the ENG gene. It does not directly change the encoded amino acid sequence of the ENG protein. It affects a nucleotide within the consensus splice site. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at