9-127825273-G-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001114753.3(ENG):c.774C>A(p.Tyr258Ter) variant causes a stop gained 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. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Y258Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001114753.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ENG | NM_001114753.3 | c.774C>A | p.Tyr258Ter | stop_gained | 6/15 | ENST00000373203.9 | |
ENG | NM_000118.4 | c.774C>A | p.Tyr258Ter | stop_gained | 6/14 | ||
ENG | NM_001278138.2 | c.228C>A | p.Tyr76Ter | stop_gained | 6/15 | ||
ENG | NM_001406715.1 | c.774C>A | p.Tyr258Ter | stop_gained | 6/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ENG | ENST00000373203.9 | c.774C>A | p.Tyr258Ter | stop_gained | 6/15 | 1 | NM_001114753.3 | P2 | |
ENG | ENST00000344849.4 | c.774C>A | p.Tyr258Ter | stop_gained | 6/14 | 1 | A2 | ||
ENG | ENST00000480266.6 | c.228C>A | p.Tyr76Ter | stop_gained | 6/15 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 27
GnomAD4 exome Cov.: 33
GnomAD4 genome ? Cov.: 27
ClinVar
Submissions by phenotype
Telangiectasia, hereditary hemorrhagic, type 1 Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Feb 02, 2022 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with hereditary hemorrhagic telangiectasia type 1 (HHT; MIM#187300). Protein truncating variants have been associated with loss of function, while missense variants have been demonstrated to have both loss of function and dominant negative effects on protein activity (PMID: 25312062) (I). 0107 - This gene is associated with autosomal dominant disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other variants predicted to cause NMD comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. It has been reported as pathogenic in ClinVar and also confirmed the clinical diagnosis of HHT in a Danish individual (PMID: 24001356). In addition, it was reported de novo in an individual with pulmonary arteriovenous malformations, thought to be the first manifestation of HHT (PMID: 34377910). (SP) 1205 - This variant has been shown to be maternally inherited (by an external laboratory). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Pathogenic, criteria provided, single submitter | research | NIHR Bioresource Rare Diseases, University of Cambridge | Jan 01, 2018 | PVS1+PM2+PP4 - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 25, 2024 | - - |
Hereditary hemorrhagic telangiectasia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 26, 2022 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 949536). This premature translational stop signal has been observed in individuals with hereditary hemorrhagic telangiectasia (PMID: 24001356; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr258*) in the ENG gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ENG are known to be pathogenic (PMID: 15879500). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at