rs116330805
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_001114753.3(ENG):c.1510G>A(p.Val504Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000922 in 1,614,110 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V504E) has been classified as Uncertain significance.
Frequency
Consequence
NM_001114753.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -20 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ENG | NM_001114753.3 | c.1510G>A | p.Val504Met | missense_variant | 12/15 | ENST00000373203.9 | |
LOC102723566 | NR_136302.1 | n.1378-15C>T | splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant | ||||
ENG | NM_000118.4 | c.1510G>A | p.Val504Met | missense_variant | 12/14 | ||
ENG | NM_001278138.2 | c.964G>A | p.Val322Met | missense_variant | 12/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ENG | ENST00000373203.9 | c.1510G>A | p.Val504Met | missense_variant | 12/15 | 1 | NM_001114753.3 | P2 | |
ENST00000439298.5 | n.1378-15C>T | splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.00294 AC: 448AN: 152208Hom.: 3 Cov.: 32
GnomAD3 exomes AF: 0.00119 AC: 298AN: 250582Hom.: 0 AF XY: 0.000981 AC XY: 133AN XY: 135608
GnomAD4 exome AF: 0.000709 AC: 1037AN: 1461784Hom.: 3 Cov.: 31 AF XY: 0.000670 AC XY: 487AN XY: 727196
GnomAD4 genome ? AF: 0.00296 AC: 451AN: 152326Hom.: 3 Cov.: 32 AF XY: 0.00278 AC XY: 207AN XY: 74478
ClinVar
Submissions by phenotype
Telangiectasia, hereditary hemorrhagic, type 1 Benign:3
Likely benign, reviewed by expert panel | curation | ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel, ClinGen | Mar 15, 2024 | The NM_001114753.3: c.1510G>A variant in ENG is a missense variant predicted to cause substitution of valine by methionine at amino acid 504 (p.Val504Met). The filtering allele frequency (the lower threshold of the 95% CI of 225/24916) of the c.1510G>A variant in ENG is 0.007757 for African/African American chromosomes by gnomAD v2.1.1, which is higher than the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel threshold (>0.002) for BS1, and therefore meets this criterion (BS1). This variant has been observed in trans with the variant c.23T>C, p.Leu8Pro (PMID: 19767588), which is classified as pathogenic by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel, in affected family members with HHT. The phase of the variants was confirmed by parental testing (BP2). The computational predictor REVEL gives a score of 0.239, which is neither above nor below the thresholds predicting a damaging or benign impact on ENG function. However, cellular assays in NIH-3T3 cells showed that BMP9 binding and BMP9 response were all normal, indicating that this variant does not impact protein function (BS3_Supporting; PMID: 25312062). 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, BP2, BS3_Supporting (specification version 1.0.0; 1/4/2024). - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 09, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 21, 2016 | - - |
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2024 | ENG: BP4, BS2 - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 11, 2018 | This variant is associated with the following publications: (PMID: 25312062, 15024723, 22022569, 20981092, 19767588, 25637381, 22995991, 24055113) - |
Haemorrhagic telangiectasia 1 Uncertain:1
Uncertain significance, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
Hereditary hemorrhagic telangiectasia Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 15, 2024 | - - |
Cardiovascular phenotype Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 16, 2016 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at