chr9-127843091-C-T
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Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_001114753.3(ENG):c.219+3G>A variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,613,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000048 ( 0 hom. )
Consequence
ENG
NM_001114753.3 splice_donor_region, intron
NM_001114753.3 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.0001222
2
Clinical Significance
Conservation
PhyloP100: 1.45
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 Likely_benign. Variant got -6 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.29).
BS2
High AC in GnomAdExome4 at 7 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ENG | NM_001114753.3 | c.219+3G>A | splice_donor_region_variant, intron_variant | ENST00000373203.9 | |||
ENG | NM_000118.4 | c.219+3G>A | splice_donor_region_variant, intron_variant | ||||
ENG | NM_001278138.2 | c.-328+3G>A | splice_donor_region_variant, intron_variant | ||||
ENG | NM_001406715.1 | c.219+3G>A | splice_donor_region_variant, intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ENG | ENST00000373203.9 | c.219+3G>A | splice_donor_region_variant, intron_variant | 1 | NM_001114753.3 | P2 | |||
ENG | ENST00000344849.4 | c.219+3G>A | splice_donor_region_variant, intron_variant | 1 | A2 | ||||
ENG | ENST00000480266.6 | c.-328+3G>A | splice_donor_region_variant, intron_variant | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152210Hom.: 0 Cov.: 31
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GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461668Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4AN XY: 727156
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GnomAD4 genome AF: 0.0000131 AC: 2AN: 152210Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74362
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Hereditary hemorrhagic telangiectasia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 13, 2021 | This sequence change falls in intron 2 of the ENG gene. It does not directly change the encoded amino acid sequence of the ENG protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ENG-related disease. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at