8-117819743-AG-A

Position:

• chr8-117819743-AG-A

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.1468delC​(p.Leu490fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,120 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: EXT1 NM_000127.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 3.06

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]

EXT1 (HGNC:):

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 8-117819743-AG-A is Pathogenic according to our data. Variant chr8-117819743-AG-A is described in ClinVar as [Pathogenic]. Clinvar id is 265130.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-117819743-AG-A is described in Lovd as [Likely_pathogenic]. Variant chr8-117819743-AG-A is described in Lovd as [Likely_pathogenic]. Variant chr8-117819743-AG-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EXT1	NM_000127.3	c.1468delC	p.Leu490fs	frameshift_variant	6/11	ENST00000378204.7	NP_000118.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EXT1	ENST00000378204.7	c.1468delC	p.Leu490fs	frameshift_variant	6/11	1	NM_000127.3	ENSP00000367446.3
EXT1	ENST00000437196.1	n.*359delC		non_coding_transcript_exon_variant	5/10	5		ENSP00000407299.1
EXT1	ENST00000684189.1	n.935delC		non_coding_transcript_exon_variant	6/11
EXT1	ENST00000437196.1	n.*359delC		3_prime_UTR_variant	5/10	5		ENSP00000407299.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461120 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726864

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Chondrosarcoma;CN263289:Exostoses, multiple, type 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Juno Genomics, Hangzhou Juno Genomics, Inc

-

PM2_Supporting+PVS1+PS4_Supporting+PP4 -

Multiple congenital exostosis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 31, 2022

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 265130). This premature translational stop signal has been observed in individuals with multiple exostoses (PMID: 10713884, 17301954). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu490Trpfs*9) 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). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 12, 2015

The c.1468delC pathogenic variant in the EXT1 gene has been reported previously in association with hereditary multiple exostoses (Dobson-Stone et al., 2000; Signori et al., 2007; Sarrión et al., 2013). The deletion causes a frameshift starting with codon Leucine 490, changes this amino acid to a Tryptophan residue and creates a premature Stop codon at position 9 of the new reading frame, denoted p.Leu490TrpfsX9. This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.1468delC variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. -

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: rs886039355; hg19: chr8-118831982;