8-117819743-AGGG-AGGGG

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.1468_1469insC(p.Leu490ProfsTer31) 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 (★★). 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:6
• 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]

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-A-AG is Pathogenic according to our data. Variant chr8-117819743-A-AG is described in ClinVar as [Pathogenic]. Clinvar id is 279804.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EXT1	NM_000127.3	c.1468_1469insC	p.Leu490ProfsTer31	frameshift_variant	6/11	ENST00000378204.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EXT1	ENST00000378204.7	c.1468_1469insC	p.Leu490ProfsTer31	frameshift_variant	6/11	1	NM_000127.3	P1
EXT1	ENST00000684189.1	n.935_936insC		non_coding_transcript_exon_variant	6/11
EXT1	ENST00000437196.1	c.*359_*360insC		3_prime_UTR_variant, NMD_transcript_variant	5/10	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple congenital exostosis Pathogenic:2

Pathogenic, flagged submission	clinical testing	Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	Mar 22, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Apr 20, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 279804). This variant is also known as c.1468insC, c.1469insC, and c.1468-1469insC. This premature translational stop signal has been observed in individuals with multiple osteochondromas (PMID: 11170095, 15586175, 17301954, 18165274). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu490Profs*31) 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:2

Pathogenic, criteria provided, single submitter	clinical testing	Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	Dec 17, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 08, 2018	This variant has been reported previously in association with hereditary multiple exostoses (Wells et al., 1997; Seki et al., 2001; Signori et al., 2007). The c.1468dupC variant causes a frameshift starting with codon Leucine 490, changes this amino acid to a Proline residue and creates a premature Stop codon at position 31 of the new reading frame, denoted p.Leu490ProfsX31. The duplication follows a polycytosine tract which is a hot spot for pathogenic variants. Frameshift variants starting from codon Leucine 490 have been observed in 7% of patients with an EXT1-related disorder (Jennes et al., 2009). The c.1468dupC 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. This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense mediated mRNA decay. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 20, 2021

- -

Exostoses, multiple, type 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

-

The frameshift duplication p.L490Pfs*31 in EXT1 (NM_000127.3) has been reported previously in individuals affected with Hereditary multiple exostoses (Seki et al, 2001; Signori et al, 2007). This variant causes a frameshift starting with codon Leucine 490, changes this amino acid to Proline residue, and creates a premature Stop codon at position 31 of the new reading frame, denoted p.Leu490ProfsTer31. The p.L490Pfs*31 variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant is predicted to cause loss of normal protein function through protein truncation caused a frameshift mutation. The frame shifted sequence continues 31 residues until a stop codon is reached. The p.L490Pfs*31 variant is a loss of function variant in the gene EXT1, which is intolerant of Loss of Function variants. For these reasons, this variant has been classified as Pathogenic. -

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;