rs1554578798

chr8-117819780-AG-Achr8-117819780-AG-AGG

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000127.3(EXT1):c.1431del(p.Ser478ProfsTer10) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P477P) has been classified as Benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EXT1 NM_000127.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: -0.248

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-117819780-AG-A is Pathogenic according to our data. Variant chr8-117819780-AG-A is described in ClinVar as [Pathogenic]. Clinvar id is 947295.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-117819780-AG-A is described in Lovd as [Likely_pathogenic]. Variant chr8-117819780-AG-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EXT1	NM_000127.3	c.1431del	p.Ser478ProfsTer10	frameshift_variant	6/11	ENST00000378204.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EXT1	ENST00000378204.7	c.1431del	p.Ser478ProfsTer10	frameshift_variant	6/11	1	NM_000127.3	P1
EXT1	ENST00000684189.1	n.898del		non_coding_transcript_exon_variant	6/11
EXT1	ENST00000437196.1	c.*322del		3_prime_UTR_variant, NMD_transcript_variant	5/10	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple congenital exostosis Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 15, 2022	ClinVar contains an entry for this variant (Variation ID: 947295). For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with multiple osteochondromatosis (PMID: 18165274, 23262345). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser478Profs*10) in the EXT1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in EXT1 are known to be pathogenic (PMID: 10679937, 11391482, 19810120). -
Pathogenic, no assertion criteria provided	clinical testing	Department of Cell Biology, School of Life Sciences, Central South University	Feb 14, 2020	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 02, 2021

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 23262345, 34012378, 18165274) -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554578798; hg19: chr8-118832019;