rs863223543
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PVS1_ModeratePM2PP3PP5_Very_Strong
The NM_001114753.3(ENG):c.1428+2T>C variant causes a splice donor 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
Genomes: not found (cov: 32)
Consequence
ENG
NM_001114753.3 splice_donor
NM_001114753.3 splice_donor
Scores
3
2
2
Splicing: ADA: 0.9816
1
1
Clinical Significance
Conservation
PhyloP100: 2.24
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 13 ACMG points.
PVS1
?
Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.05867476 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, max_spliceai. No scorers claiming Uncertain. Scorers claiming Benign: dbscSNV1_RF.
PP5
?
Variant 9-127818714-A-G is Pathogenic according to our data. Variant chr9-127818714-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 213217.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.1428+2T>C | splice_donor_variant | ENST00000373203.9 | |||
LOC102723566 | NR_136302.1 | n.1568+3A>G | splice_donor_region_variant, intron_variant, non_coding_transcript_variant | ||||
ENG | NM_000118.4 | c.1428+2T>C | splice_donor_variant | ||||
ENG | NM_001278138.2 | c.882+2T>C | splice_donor_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ENG | ENST00000373203.9 | c.1428+2T>C | splice_donor_variant | 1 | NM_001114753.3 | P2 | |||
ENST00000439298.5 | n.1568+3A>G | splice_donor_region_variant, intron_variant, non_coding_transcript_variant | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 07, 2015 | 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 - |
Hereditary hemorrhagic telangiectasia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 17, 2021 | This variant is not present in population databases (ExAC no frequency). 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). Disruption of this splice site has been observed in individuals with hereditary hemorrhagic telangiectasia (PMID: 16752392, 22991266). 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). - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 26, 2018 | 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. Another alteration affecting this nucleotide has been reported in association with hereditary hemorrhagic telangiectasia (Bossler AD et al. Hum Mutat. 2006 Jul;27(7):667-75). 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Benign
D
MutationTaster
Benign
D;D;D;D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: 2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at