rs886039505
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_001114753.3(ENG):c.360+1G>T variant causes a splice donor, 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 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_001114753.3 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ENG | NM_001114753.3 | c.360+1G>T | splice_donor_variant, intron_variant | Intron 3 of 14 | ENST00000373203.9 | NP_001108225.1 | ||
ENG | NM_000118.4 | c.360+1G>T | splice_donor_variant, intron_variant | Intron 3 of 13 | NP_000109.1 | |||
ENG | NM_001278138.2 | c.-187+1G>T | splice_donor_variant, intron_variant | Intron 3 of 14 | NP_001265067.1 | |||
ENG | NM_001406715.1 | c.360+1G>T | splice_donor_variant, intron_variant | Intron 3 of 7 | NP_001393644.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ENG | ENST00000373203.9 | c.360+1G>T | splice_donor_variant, intron_variant | Intron 3 of 14 | 1 | NM_001114753.3 | ENSP00000362299.4 | |||
ENG | ENST00000344849.4 | c.360+1G>T | splice_donor_variant, intron_variant | Intron 3 of 13 | 1 | ENSP00000341917.3 | ||||
ENG | ENST00000480266.6 | c.-187+1G>T | splice_donor_variant, intron_variant | Intron 3 of 14 | 2 | ENSP00000479015.1 | ||||
ENG | ENST00000462196.1 | n.118+1G>T | splice_donor_variant, intron_variant | Intron 1 of 3 | 3 | ENSP00000519251.1 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Hereditary hemorrhagic telangiectasia Pathogenic:1
This sequence change affects a donor splice site in intron 3 of the ENG 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 ENG are known to be pathogenic (PMID: 15879500). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with hereditary hemorrhagic telangiectasia (PMID: 9366572, 11793473, 12920067, 22991266). This variant is also known as IVS3+1, gt. ClinVar contains an entry for this variant (Variation ID: 947881). 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. -
Cardiovascular phenotype Pathogenic:1
The c.360+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 3 of the ENG gene. This mutation has been described in an individual with a clinical diagnosis of hereditary hemorrhagic telangiectasia (Berg J, J. Med. Genet. 2003 Aug; 40(8):585-90). However, specific clinical information was not provided. Another pathogenic mutation (c.360+1G>A) has been described at the same nucleotide position (Kim et al 2011, BMC Med Genet 12:130). In addition to the clinical data presented in the literature, since alterations that disrupt the canonical splice donor site are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at