Variant 8-117819742-CA-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000127.3(EXT1):c.1469delT(p.Leu490fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,122 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: 6.8e-7 ( 0 hom. )

Consequence

EXT1
NM_000127.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 8.87

Variant links:

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 links:

EXT1 (HGNC:):

EXT1 links:

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ACMG classification

Classification made for transcript

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 8-117819742-CA-C is Pathogenic according to our data. Variant chr8-117819742-CA-C is described in ClinVar as [Pathogenic]. Clinvar id is 265131.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-117819742-CA-C is described in Lovd as [Likely_pathogenic]. Variant chr8-117819742-CA-C is described in Lovd as [Pathogenic]. Variant chr8-117819742-CA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EXT1	NM_000127.3 linkuse as main transcript	c.1469delT	p.Leu490fs	frameshift_variant	6/11	ENST00000378204.7	NP_000118.2	Q16394

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
EXT1	ENST00000378204.7 linkuse as main transcript	c.1469delT	p.Leu490fs	frameshift_variant	6/11	1	NM_000127.3	ENSP00000367446.3	Q16394
EXT1	ENST00000437196.1 linkuse as main transcript	n.*360delT		non_coding_transcript_exon_variant	5/10	5		ENSP00000407299.1	F8WF54
EXT1	ENST00000684189.1 linkuse as main transcript	n.936delT		non_coding_transcript_exon_variant	6/11
EXT1	ENST00000437196.1 linkuse as main transcript	n.*360delT		3_prime_UTR_variant	5/10	5		ENSP00000407299.1	F8WF54

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461122

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726870

show subpopulations

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Exostoses, multiple, type 1

Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Mar 24, 2022	PVS1, PM2, PP3, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The observed frameshift variant c.1469del (p.Leu490ArgfsTer9) in EXT1 gene has been reported in heterozygous state in multiple individuals affected with Exostoses (Kim S et al. 2022; Mohaidat Z et al. 2021; Santos SCL et al. 2018). The p.Leu490ArgfsTer9 variant is absent in gnomAD Exomes. This variant has been submitted to the ClinVar database as Pathogenic (multiple submitters). This variant causes a frameshift starting with codon Leucine 490, changes this amino acid to Arginine residue, and creates a premature Stop codon at position 9 of the new reading frame, denoted p.Leu490ArgfsTer9. This variant is predicted to cause loss of normal protein function through protein truncation. Loss-of-function variants in EXT1 are known to be pathogenic (Jennes I et al. 2009). For these reasons, this variant has been classified as Pathogenic -
Pathogenic, criteria provided, single submitter	not provided	Institute of Human Genetics, University Hospital of Duesseldorf	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Human Genetics, Hannover Medical School	Jul 30, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 1995	- -
Pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Sep 26, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Dec 14, 2022	PVS1, PS4, PM2, PM6 -

Chondrosarcoma

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Dec 12, 2023

- -

Multiple congenital exostosis

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 22, 2023

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 265131). This premature translational stop signal has been observed in individuals with multiple osteochondromas and hereditary multiple osteochondromas (PMID: 7550340, 23439489, 29126381). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu490Argfs*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

Nov 17, 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 in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 23439489, 10679937, 29529714, 23262345, 18165274, 16088908, 9326317, 11432960, 17301954, 9150727, 9463333, 10480354, 7550340, 21039224, 29126381, 19810120, 11391482, 30334991, 30806661, 33632255, 32293802, 33552269) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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