8-117837105-T-G

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

Scores

2
Splicing: ADA: 0.9994
2

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.75
Variant links:
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
EXT1NM_000127.3 linkuse as main transcriptc.1056+3A>C splice_donor_region_variant, intron_variant ENST00000378204.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
EXT1ENST00000378204.7 linkuse as main transcriptc.1056+3A>C splice_donor_region_variant, intron_variant 1 NM_000127.3 P1
EXT1ENST00000436216.2 linkuse as main transcriptc.424+3A>C splice_donor_region_variant, intron_variant, NMD_transcript_variant 3
EXT1ENST00000437196.1 linkuse as main transcriptc.74-1554A>C intron_variant, NMD_transcript_variant 5
EXT1ENST00000684189.1 linkuse as main transcriptn.523+3A>C splice_donor_region_variant, intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
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 submitterclinical testingInvitaeMay 17, 2017This 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.25
CADD
Benign
22
DANN
Benign
0.96
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.8

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.97
SpliceAI score (max)
0.48
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.48
Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1554580140; hg19: chr8-118849344; API