rs1060501414
Variant summary
Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PM2PP3_StrongPP5_Very_Strong
The NM_001114753.3(ENG):c.524-2A>G variant causes a splice acceptor change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,164 control chromosomes in the GnomAD database, with no homozygous occurrence. 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_acceptor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 22 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ENG | NM_001114753.3 | c.524-2A>G | splice_acceptor_variant | ENST00000373203.9 | |||
ENG | NM_000118.4 | c.524-2A>G | splice_acceptor_variant | ||||
ENG | NM_001278138.2 | c.-23-2A>G | splice_acceptor_variant | ||||
ENG | NM_001406715.1 | c.524-2A>G | splice_acceptor_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ENG | ENST00000373203.9 | c.524-2A>G | splice_acceptor_variant | 1 | NM_001114753.3 | P2 | |||
ENG | ENST00000344849.4 | c.524-2A>G | splice_acceptor_variant | 1 | A2 | ||||
ENG | ENST00000480266.6 | c.-23-2A>G | splice_acceptor_variant | 2 | |||||
ENG | ENST00000462196.1 | n.424-2A>G | splice_acceptor_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152164Hom.: 0 Cov.: 32
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1435346Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0AN XY: 711822
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152164Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74330
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 29, 2023 | Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22385575, 8162075, 21158752, 15879500, 20656886, 9554745, 32300199, 17384219) - |
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Mar 31, 2021 | PVS1, PM2, PP1_strong - |
Telangiectasia, hereditary hemorrhagic, type 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jun 19, 2023 | The ENG c.524-2A>G variant (rs1060501414) is reported in the literature in multiple individuals affected with hemorrhagic telangiectasia (Gallione 1998, Bayrak-Toydemir 2006, Gedge 2007, McDonald 2011, McDonald 2020). This variant is also reported in ClinVar (Variation ID: 407119). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant disrupts the canonical splice acceptor site of intron four, which is likely to negatively impact gene function. Based on available information, this variant is considered to be pathogenic. References: Bayrak-Toydemir P et al. Genotype-phenotype correlation in hereditary hemorrhagic telangiectasia: mutations and manifestations. Am J Med Genet A. 2006 Mar 1;140(5):463-70. PMID: 16470787. Gallione CJ et al. Mutation and expression analysis of the endoglin gene in hereditary hemorrhagic telangiectasia reveals null alleles. Hum Mutat. 1998;11(4):286-94. PMID: 9554745. Gedge F et al. Clinical and analytical sensitivities in hereditary hemorrhagic telangiectasia testing and a report of de novo mutations. J Mol Diagn. 2007 Apr;9(2):258-65. PMID: 17384219. McDonald J et al. Molecular diagnosis in hereditary hemorrhagic telangiectasia: findings in a series tested simultaneously by sequencing and deletion/duplication analysis. Clin Genet. 2011 Apr;79(4):335-44. PMID: 21158752. McDonald J et al. Curaçao diagnostic criteria for hereditary hemorrhagic telangiectasia is highly predictive of a pathogenic variant in ENG or ACVRL1 (HHT1 and HHT2). Genet Med. 2020 Jul;22(7):1201-1205. PMID: 32300199. - |
ENG-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 20, 2024 | The ENG c.524-2A>G variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant has been reported in multiple individuals with hereditary hemorrhagic telangiectasia (HHT) (Gallione et al. 1998. PubMed ID: 9554745; Table S1, McDonald et al. 2020. PubMed ID: 32300199; Gedge et al. 2007. PubMed ID: 17384219). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Variants that disrupt the consensus splice acceptor site in ENG are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 17, 2024 | The c.524-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 5 in the ENG gene. This alteration was first was described in a family with hereditary hemorrhagic telangiectasia (HHT) and reportedly segregated with disease (Gallione CJ et al. Hum. Mutat., 1998;11:286-94). This alteration was also described in two unrelated individuals with a clinical diagnosis of HHT (Gedge F et al. J Mol Diagn, 2007 Apr;9:258-65). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. - |
Hereditary hemorrhagic telangiectasia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 16, 2024 | This sequence change affects an acceptor splice site in intron 4 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 hemorrhagic telangiectasia (PMID: 8162075, 9554745, 21158752). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 407119). 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