9-127826641-G-A
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1
This summary comes from the ClinGen Evidence Repository: The NM_001114753.3: c.392C>T variant in ENG is a missense variant predicted to cause substitution of proline by leucine at amino acid 131 (p.Pro131Leu). The filtering allele frequency (the lower threshold of the 95% CI of 762/30612) of the c.392C>T variant in ENG is 0.02343 for South Asian chromosomes by gnomAD v2.1.1, which is higher than the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel threshold (>0.01) for BA1, and therefore meets this criterion (BA1). The computational predictor REVEL gives a score of 0.315, which is neither above nor below the thresholds predicting a damaging or benign impact on ENG function. In summary, this variant meets the criteria to be classified as benign for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: BA1 (specification version 1.0.0; 1/4/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA202695/MONDO:0008535/136
Frequency
Consequence
NM_001278138.2 5_prime_UTR_premature_start_codon_gain
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ENG | NM_001114753.3 | c.392C>T | p.Pro131Leu | missense_variant | Exon 4 of 15 | ENST00000373203.9 | NP_001108225.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00193 AC: 294AN: 152082Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00461 AC: 1158AN: 251006Hom.: 10 AF XY: 0.00590 AC XY: 800AN XY: 135674
GnomAD4 exome AF: 0.00274 AC: 4012AN: 1461634Hom.: 49 Cov.: 32 AF XY: 0.00345 AC XY: 2510AN XY: 727110
GnomAD4 genome AF: 0.00193 AC: 293AN: 152200Hom.: 0 Cov.: 32 AF XY: 0.00226 AC XY: 168AN XY: 74412
ClinVar
Submissions by phenotype
Telangiectasia, hereditary hemorrhagic, type 1 Benign:3
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
The NM_001114753.3: c.392C>T variant in ENG is a missense variant predicted to cause substitution of proline by leucine at amino acid 131 (p.Pro131Leu). The filtering allele frequency (the lower threshold of the 95% CI of 762/30612) of the c.392C>T variant in ENG is 0.02343 for South Asian chromosomes by gnomAD v2.1.1, which is higher than the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel threshold (>0.01) for BA1, and therefore meets this criterion (BA1). The computational predictor REVEL gives a score of 0.315, which is neither above nor below the thresholds predicting a damaging or benign impact on ENG function. In summary, this variant meets the criteria to be classified as benign for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: BA1 (specification version 1.0.0; 1/4/2024). -
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not specified Benign:2
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not provided Benign:2
ENG: BP4, BS1, BS2 -
This variant is associated with the following publications: (PMID: 32560555, 28655553, 27535533, 27146957, 12673790, 15879500, 25637381, 23399955, 21158752, 24055113) -
Haemorrhagic telangiectasia 1 Uncertain:1
Low GERP score may suggest that this variant may belong in a lower pathogenicity class -
Galloway-Mowat syndrome 1 Benign:1
The heterozygous p.Pro131Leu variant in ENG has been identified in multiple individuals with haemorrhagic telangiectasia and individuals without haemorrhagic telangiectasia (PMID: 15879500, 21158752), and has been identified in >2% of South Asian chromosomes and 7 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for autosomal dominant haemorrhagic telangiectasia. -
Cardiovascular phenotype Benign:1
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Hereditary hemorrhagic telangiectasia Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at