NM_000127.3:c.1016G>A

Variant names:

• chr8-117837148-C-T
• rs119103288
• NM_000127.3:c.1016G>A

Variant summary

Our verdict is Pathogenic. The variant received 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. G339V) 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
• Publications: 9 publications found

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 Gene-Disease associations (from GenCC):

• exostoses, multiple, type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen
• chondrosarcoma

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• hereditary multiple osteochondromas

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PM1: In a hotspot region, there are 16 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 chr8-117837148-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 2735203.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 VariationId is 2498.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000127.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EXT1	NM_000127.3	MANE Select	c.1016G>A	p.Gly339Asp	missense	Exon 2 of 11	NP_000118.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EXT1	ENST00000378204.7	TSL:1 MANE Select	c.1016G>A	p.Gly339Asp	missense	Exon 2 of 11	ENSP00000367446.3
	EXT1	ENST00000436216.2	TSL:3	n.383G>A		non_coding_transcript_exon	Exon 2 of 6	ENSP00000400372.1
	EXT1	ENST00000684189.1		n.483G>A		non_coding_transcript_exon	Exon 2 of 11

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple congenital exostosis Pathogenic:1

Nov 25, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This variant is not present in population databases (ExAC no frequency). 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). 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). For these reasons, this variant has been classified as Pathogenic.

not provided Pathogenic:1

Jun 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Exostoses, multiple, type 1 Pathogenic:1

Jun 01, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		7.9
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
Mutation Taster		=2/98	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs119103288; hg19: chr8-118849387;