rs1554656288

chr8-117799893-GA-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_000127.3(EXT1):c.2059del(p.Ser687LeufsTer19) variant causes a frameshift 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 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.29

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 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 13 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-117799893-GA-G is Pathogenic according to our data. Variant chr8-117799893-GA-G is described in ClinVar as [Pathogenic]. Clinvar id is 526309.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.2059del	p.Ser687LeufsTer19	frameshift_variant	11/11	ENST00000378204.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EXT1	ENST00000378204.7	c.2059del	p.Ser687LeufsTer19	frameshift_variant	11/11	1	NM_000127.3	P1
EXT1	ENST00000684189.1	n.1526del		non_coding_transcript_exon_variant	11/11
EXT1	ENST00000684443.1	n.2185del		non_coding_transcript_exon_variant	2/2
EXT1	ENST00000437196.1	c.*950del		3_prime_UTR_variant, NMD_transcript_variant	10/10	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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

Invitae

Oct 06, 2017

For these reasons, this variant has been classified as Pathogenic. Different truncations (p.Arg701*, p.Gln702*) located downstream of this variant has been determined to be pathogenic (PMID: 11170095, 26690531, 19810120, Invitae). This suggests that deletion of this region of the EXT1 protein is causative of disease. This variant has not been reported in the literature in individuals with EXT1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the EXT1 gene (p.Ser687Leufs*19). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 60 amino acids of the EXT1 protein. -

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: rs1554656288; hg19: chr8-118812132;