rs119103288

Positions:

• chr8-117837148-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000127.3(EXT1):​c.1016G>A​(p.Gly339Asp) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G339S) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EXT1 NM_000127.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.90

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.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000127.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-117837149-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 1066566.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 8-117837148-C-T is Pathogenic according to our data. Variant chr8-117837148-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 2498.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-117837148-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EXT1	NM_000127.3	c.1016G>A	p.Gly339Asp	missense_variant	2/11	ENST00000378204.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EXT1	ENST00000378204.7	c.1016G>A	p.Gly339Asp	missense_variant	2/11	1	NM_000127.3	P1
EXT1	ENST00000684189.1	n.483G>A		non_coding_transcript_exon_variant	2/11
EXT1	ENST00000436216.2	c.386G>A	p.Gly129Asp	missense_variant, NMD_transcript_variant	2/6	3
EXT1	ENST00000437196.1	c.74-1597G>A		intron_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple congenital exostosis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 25, 2020

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change abolishes heparan sulfate biosynthesis and disrupts the activity of the EXT1/EXT2 protein complex (PMID: 10639137, 9620772). This variant has been observed in several individuals affected with hereditary multiple osteochondromatosis (PMID: 9326317, 23439489, Invitae). ClinVar contains an entry for this variant (Variation ID: 2498). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with aspartic acid at codon 339 of the EXT1 protein (p.Gly339Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2023

EXT1: PM1, PM2, PM5, PS4:Moderate, PP1, PP3, PP4, PS3:Supporting -

Exostoses, multiple, type 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 1998

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.24	D
MutationAssessor	Pathogenic	3.8	H
MutationTaster	Benign	1.0	A
PrimateAI	Pathogenic	0.95	D
PROVEAN	Pathogenic	-5.2	D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.98		Gain of relative solvent accessibility (P = 0.0215);
MVP		0.97
MPC		1.4
ClinPred		1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.76
gMVP		0.99

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: rs119103288; hg19: chr8-118849387;