8-118110690-G-T

Position:

• chr8-118110690-G-T

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.357C>A​(p.Tyr119*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EXT1 NM_000127.3 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 6.73

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 8-118110690-G-T is Pathogenic according to our data. Variant chr8-118110690-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2499.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-118110690-G-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EXT1	NM_000127.3	c.357C>A	p.Tyr119*	stop_gained	1/11	ENST00000378204.7	NP_000118.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EXT1	ENST00000378204.7	c.357C>A	p.Tyr119*	stop_gained	1/11	1	NM_000127.3	ENSP00000367446.3
EXT1	ENST00000437196.1	n.73+284C>A		intron_variant		5		ENSP00000407299.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Exostoses, multiple, type 1 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The stop gained c.357C>A (p.Tyr119Ter) variant in the EXT1 gene has been reported previously in a patient with multiple osteochondromas (Raskind et al., 1998). This variant is absent in the gnomAD Exomes. It is submitted to ClinVar as Pathogenic. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Loss of function variants have been previously reported to be disease causing. The nucleotide change c.357C>A in EXT1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Evidence in multiple individuals and additional studies are required to prove the pathogenicity of the variant. For these reasons, this variant has been classified as Likely Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1998	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 13, 2022

Reported in a patient with multiple osteochondromas in published literature (Raskind et al., 1998); however, clinical data is limited; Nonsense 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 (gnomAD); This variant is associated with the following publications: (PMID: 10679937, 9521425) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Uncertain	0.77	D
Vest4		0.93
GERP RS		5.5

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: rs119103289; hg19: chr8-119122929;