9-127818173-C-T
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BS1_SupportingBP2BP5
This summary comes from the ClinGen Evidence Repository: The NM_001114753.3: c.1633G>A variant in ENG is a missense variant predicted to cause substitution of glycine by serine at amino acid 545 (p.Gly545Ser). The filtering allele frequency (the lower threshold of the 95% CI of 54/35,428 alleles) of the c.1633G>A variant in ENG is 0.1% for Admixed American chromosomes by gnomAD v2.1.1, which is higher than the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel threshold (>0.08%) for BS1_Supporting, and therefore meets this criterion (BS1_Supporting). This variant has been observed in trans with the variant c.391_392del, p.(Pro131Glyfs*17) (PMID:18498373) which is classified as likely pathogenic (PMID:18498373) in an individual with hereditary hemorrhagic telangiectasia. The phase of the variants was confirmed by family testing (BP2). This variant has been observed in at least two patients with an alternate molecular basis for disease (likely pathogenic/pathogenic variants identified in ACVRL1) (BP5; internal lab contributors). The computational predictor REVEL gives a score of 0.399, 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 likely 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: BS1_Supporting, BP2, BP5 (specifications version 1.1.0; 09/11/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA5252712/MONDO:0008535/136
Frequency
Consequence
NM_001114753.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ENG | NM_001114753.3 | c.1633G>A | p.Gly545Ser | missense_variant | Exon 12 of 15 | ENST00000373203.9 | NP_001108225.1 | |
ENG | NM_000118.4 | c.1633G>A | p.Gly545Ser | missense_variant | Exon 12 of 14 | NP_000109.1 | ||
ENG | NM_001278138.2 | c.1087G>A | p.Gly363Ser | missense_variant | Exon 12 of 15 | NP_001265067.1 | ||
LOC102723566 | NR_136302.1 | n.1378-138C>T | intron_variant | Intron 2 of 5 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000361 AC: 55AN: 152194Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000521 AC: 131AN: 251296Hom.: 0 AF XY: 0.000456 AC XY: 62AN XY: 135870
GnomAD4 exome AF: 0.000666 AC: 973AN: 1461876Hom.: 2 Cov.: 31 AF XY: 0.000660 AC XY: 480AN XY: 727242
GnomAD4 genome AF: 0.000361 AC: 55AN: 152312Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18AN XY: 74476
ClinVar
Submissions by phenotype
Telangiectasia, hereditary hemorrhagic, type 1 Benign:3
European Non-Finnish population allele frequency is 0.12% (rs142896669, 54/35,428 alleles, 0 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.4.1, this variant is classified as LIKELY BENIGN. Following criteria are met: BS1 -
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
The NM_001114753.3: c.1633G>A variant in ENG is a missense variant predicted to cause substitution of glycine by serine at amino acid 545 (p.Gly545Ser). The filtering allele frequency (the lower threshold of the 95% CI of 54/35,428 alleles) of the c.1633G>A variant in ENG is 0.1% for Admixed American chromosomes by gnomAD v2.1.1, which is higher than the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel threshold (>0.08%) for BS1_Supporting, and therefore meets this criterion (BS1_Supporting). This variant has been observed in trans with the variant c.391_392del, p.(Pro131Glyfs*17) (PMID: 18498373) which is classified as likely pathogenic (PMID: 18498373) in an individual with hereditary hemorrhagic telangiectasia. The phase of the variants was confirmed by family testing (BP2). This variant has been observed in at least two patients with an alternate molecular basis for disease (likely pathogenic/pathogenic variants identified in ACVRL1) (BP5; internal lab contributors). The computational predictor REVEL gives a score of 0.399, 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 likely 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: BS1_Supporting, BP2, BP5 (specifications version 1.1.0; 09/11/2024). -
Pulmonary hypertension, primary, 1 Pathogenic:1
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not specified Uncertain:1
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 2 probands, no segs in HGMD; ExAC: 0.2% (25/11560) Latino chromosomes -
Pulmonary arterial hypertension associated with congenital heart disease Uncertain:1
- -
ENG-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
not provided Benign:1
See Variant Classification Assertion Criteria. -
Hereditary hemorrhagic telangiectasia Benign:1
- -
Cardiovascular phenotype Benign:1
This alteration is classified as likely 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at