rs1554580140
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3PP5_Moderate
The NM_000127.3(EXT1):c.1056+3A>C variant causes a splice donor region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: not found (cov: 32)
Consequence
EXT1
NM_000127.3 splice_donor_region, intron
NM_000127.3 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.9994
2
Clinical Significance
Conservation
PhyloP100: 7.75
Genes affected
EXT1 (HGNC:3512): (exostosin glycosyltransferase 1) This gene encodes an endoplasmic reticulum-resident type II transmembrane glycosyltransferase involved in the chain elongation step of heparan sulfate biosynthesis. Mutations in this gene cause the type I form of multiple exostoses. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 5 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
PP5
?
Variant 8-117837105-T-G is Pathogenic according to our data. Variant chr8-117837105-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 456060.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EXT1 | NM_000127.3 | c.1056+3A>C | splice_donor_region_variant, intron_variant | ENST00000378204.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EXT1 | ENST00000378204.7 | c.1056+3A>C | splice_donor_region_variant, intron_variant | 1 | NM_000127.3 | P1 | |||
EXT1 | ENST00000436216.2 | c.424+3A>C | splice_donor_region_variant, intron_variant, NMD_transcript_variant | 3 | |||||
EXT1 | ENST00000437196.1 | c.74-1554A>C | intron_variant, NMD_transcript_variant | 5 | |||||
EXT1 | ENST00000684189.1 | n.523+3A>C | splice_donor_region_variant, intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Multiple congenital exostosis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 17, 2017 | This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of nucleotide changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. This variant has been reported in an individual affected with multiple osteochondromas (PMID: 19810120). Family studies have also indicated that this variant segregates with multiple osteochondromas in a family (Invitae). This sequence change falls in intron 2 of the EXT1 gene. It does not directly change the encoded amino acid sequence of the EXT1 protein, but it affects a nucleotide within the consensus splice site of the intron. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
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_DL_spliceai
Position offset: 3
Find out detailed SpliceAI scores and Pangolin per-transcript scores at