rs1554657940

Positions:

• chr8-117812923-GATGATGTTGTCGTAGGGCAGAAAACGGCTGCTCATAACCTGGGAGGAAGTAGAAGTAGGCAGTGGGGAGGGA-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_000127.3(EXT1):​c.1633-34_1670del variant causes a splice acceptor, coding sequence, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EXT1 NM_000127.3 splice_acceptor, coding_sequence, intron
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.04

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]

ACMG classification

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 0.039714415 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-117812923-GATGATGTTGTCGTAGGGCAGAAAACGGCTGCTCATAACCTGGGAGGAAGTAGAAGTAGGCAGTGGGGAGGGA-G is Pathogenic according to our data. Variant chr8-117812923-GATGATGTTGTCGTAGGGCAGAAAACGGCTGCTCATAACCTGGGAGGAAGTAGAAGTAGGCAGTGGGGAGGGA-G is described in ClinVar as [Pathogenic]. Clinvar id is 456063.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EXT1	NM_000127.3	c.1633-34_1670del		splice_acceptor_variant, coding_sequence_variant, intron_variant	8/11	ENST00000378204.7	NP_000118.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EXT1	ENST00000378204.7	c.1633-34_1670del		splice_acceptor_variant, coding_sequence_variant, intron_variant	8/11	1	NM_000127.3	ENSP00000367446	P1
EXT1	ENST00000684189.1	n.1100-34_1137del		splice_acceptor_variant, non_coding_transcript_exon_variant, intron_variant	8/11
EXT1	ENST00000437196.1	c.*524-34_*561del		splice_acceptor_variant, 3_prime_UTR_variant, intron_variant, NMD_transcript_variant	7/10	5		ENSP00000407299

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Multiple congenital exostosis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 10, 2017

This variant is a gross deletion of the genomic region encompassing part of exon 8 of the EXT1 gene, including the intron 7-exon 8 boundary (c.1633-34_1670del). This likely creates a premature translational stop signal and is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). Loss-of-function variants in EXT1 are known to be pathogenic (PMID: 10679937, 11391482, 19810120). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554657940; hg19: chr8-118825162;