rs764038221
Variant names:
Your query was ambiguous. Multiple possible variants found:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_ModeratePM2PP5_Moderate
The NM_019055.6(ROBO4):c.2056+1G>T variant causes a splice donor, intron 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. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Genomes: not found (cov: 33)
Consequence
ROBO4
NM_019055.6 splice_donor, intron
NM_019055.6 splice_donor, intron
Scores
4
2
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 2.47
Genes affected
ROBO4 (HGNC:17985): (roundabout guidance receptor 4) Predicted to enable cell-cell adhesion mediator activity. Involved in angiogenesis and establishment of endothelial barrier. Located in extracellular exosome. Implicated in aortic valve disease 3. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.035714287 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.7, offset of 33, new splice context is: gggGTgaga. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 11-124887732-C-A is Pathogenic according to our data. Variant chr11-124887732-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 560404.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ROBO4 | NM_019055.6 | c.2056+1G>T | splice_donor_variant, intron_variant | Intron 13 of 17 | ENST00000306534.8 | NP_061928.4 | ||
| ROBO4 | NM_001301088.2 | c.1621+1G>T | splice_donor_variant, intron_variant | Intron 13 of 17 | NP_001288017.1 | |||
| ROBO4 | XM_006718861.3 | c.2056+1G>T | splice_donor_variant, intron_variant | Intron 13 of 17 | XP_006718924.1 | |||
| ROBO4 | XM_011542875.2 | c.730+1G>T | splice_donor_variant, intron_variant | Intron 6 of 10 | XP_011541177.1 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Bicuspid aortic valve;C0856747:Ascending tubular aorta aneurysm Pathogenic:1
-
Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: research
- -
Aortic valve disease 3 Pathogenic:1
Jul 09, 2019
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only
- -
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: 46
DS_DL_spliceai
Position offset: 1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at