rs878853659
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PM2PP3_StrongPP5_Very_Strong
The NM_001114753.3(ENG):c.68-1G>A variant causes a splice acceptor change. The variant allele was found at a frequency of 0.000000684 in 1,461,852 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 Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 30)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
ENG
NM_001114753.3 splice_acceptor
NM_001114753.3 splice_acceptor
Scores
4
2
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 3.60
Genes affected
ENG (HGNC:3349): (endoglin) This gene encodes a homodimeric transmembrane protein which is a major glycoprotein of the vascular endothelium. This protein is a component of the transforming growth factor beta receptor complex and it binds to the beta1 and beta3 peptides with high affinity. Mutations in this gene cause hereditary hemorrhagic telangiectasia, also known as Osler-Rendu-Weber syndrome 1, an autosomal dominant multisystemic vascular dysplasia. This gene may also be involved in preeclampsia and several types of cancer. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2013]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 22 ACMG points.
PVS1
?
Splicing variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 9-127843246-C-T is Pathogenic according to our data. Variant chr9-127843246-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 237030.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ENG | NM_001114753.3 | c.68-1G>A | splice_acceptor_variant | ENST00000373203.9 | |||
ENG | NM_000118.4 | c.68-1G>A | splice_acceptor_variant | ||||
ENG | NM_001278138.2 | c.-479-1G>A | splice_acceptor_variant | ||||
ENG | NM_001406715.1 | c.68-1G>A | splice_acceptor_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ENG | ENST00000373203.9 | c.68-1G>A | splice_acceptor_variant | 1 | NM_001114753.3 | P2 | |||
ENG | ENST00000344849.4 | c.68-1G>A | splice_acceptor_variant | 1 | A2 | ||||
ENG | ENST00000480266.6 | c.-479-1G>A | splice_acceptor_variant | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 30
GnomAD3 genomes
?
Cov.:
30
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461852Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727236
GnomAD4 exome
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32
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AN XY:
727236
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GnomAD4 genome ? Cov.: 30
GnomAD4 genome
?
Cov.:
30
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Telangiectasia, hereditary hemorrhagic, type 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 08, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); 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; This variant is associated with the following publications: (PMID: 25525159, 16752392, 15024723) - |
Hereditary hemorrhagic telangiectasia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 17, 2016 | For these reasons, this variant has been classified as Pathogenic. Truncating variants in ENG are known to be pathogenic (PMID: 21158752, 12673790). This particular variant has been identified in a patient with confirmed hereditary hemorrhagic telangiectasia (PMID: 15024723). This sequence change affects an acceptor splice site in intron 1 of the ENG gene. It is expected to disrupt mRNA splicing and likely results in an absent or disrupted protein product. - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 12, 2021 | The c.68-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 2 of 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 acceptor site and may result in the creation or strengthening of a novel splice acceptor site. The stop codon in the predicted resulting transcript occurs within the first 150 nucleotides ofthe ENG gene. As such, this alteration may escape nonsense-mediated mRNAdecay and/or be prone to rescue by reinitiation (Rivas et al. Science. 2015 May 8;348(6235):666-9; Lindeboom et al. Nat Genet. 2016 Oct;48(10):1112-8; Rhee et al. Sci Rep. 2017 May 10;7(1):1653). The exact functional effect of this alteration is unknown; however, the impacted region is critical for protein function (Ambry internal data). This alteration has been observed in individuals with personal and family histories of hereditary hemorrhagic telangiectasia (HHT) (Ambry internal data; Lesca G et al. Hum Mutat, 2004 Apr;23:289-99). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
D;D;D;D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: -2
DS_AL_spliceai
Position offset: -1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at