rs863223543
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_001114753.3(ENG):c.1428+2T>C 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. 2/3 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.1428+2T>C | splice_donor_variant, intron_variant | Intron 11 of 14 | ENST00000373203.9 | NP_001108225.1 | ||
ENG | NM_000118.4 | c.1428+2T>C | splice_donor_variant, intron_variant | Intron 11 of 13 | NP_000109.1 | |||
ENG | NM_001278138.2 | c.882+2T>C | splice_donor_variant, intron_variant | Intron 11 of 14 | NP_001265067.1 | |||
LOC102723566 | NR_136302.1 | n.1568+3A>G | splice_region_variant, intron_variant | Intron 4 of 5 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:1
c.1428+2 T>C: IVS11+2 T>C in intron 11 of the ENG gene (NM_000118.2) Although the c.1428+2 T>C mutation has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge, a mutation affecting the same nucleotide, c.1428+2 T>G, has been reported in association with HHT (Bossler A et al., 2006). The c.1428+2 T>C mutation was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This mutation destroys the canonical splice donor site in intron 11 and is predicted to cause abnormal gene splicing. Furthermore, other splice site mutations in the ENG gene have been reported in association with HHT. In summary, c.1428+2 T>C in the ENG gene is interpreted as a disease-causing mutation. This variant was found in HHT-ARRHYTHMIA,ENG -
Cardiovascular phenotype Pathogenic:1
The c.1428+2T>C intronic pathogenic mutation results from a T to C substitution two nucleotides after coding exon 11 in the ENG gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown; however, the impacted region is critical for protein function (Ambry internal data). This variant has been observed in at least one individual with a personal and/or family history that is consistent with hereditary hemorrhagic telangiectasia (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. -
Hereditary hemorrhagic telangiectasia Pathogenic:1
This sequence change affects a donor splice site in intron 11 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). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 213217). Disruption of this splice site has been observed in individuals with hereditary hemorrhagic telangiectasia (PMID: 16752392, 22991266). This variant is not present in population databases (ExAC no frequency). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at