rs1554656266

chr8-117799849-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_000127.3(EXT1):c.2104C>T(p.Gln702Ter) variant causes a stop gained 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 (★). Synonymous variant affecting the same amino acid position (i.e. Q702Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EXT1 NM_000127.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 10.0

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 Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 7 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-117799849-G-A is Pathogenic according to our data. Variant chr8-117799849-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 526307.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-117799849-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EXT1	NM_000127.3	c.2104C>T	p.Gln702Ter	stop_gained	11/11	ENST00000378204.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EXT1	ENST00000378204.7	c.2104C>T	p.Gln702Ter	stop_gained	11/11	1	NM_000127.3	P1
EXT1	ENST00000684189.1	n.1571C>T		non_coding_transcript_exon_variant	11/11
EXT1	ENST00000684443.1	n.2230C>T		non_coding_transcript_exon_variant	2/2
EXT1	ENST00000437196.1	c.*995C>T		3_prime_UTR_variant, NMD_transcript_variant	10/10	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Multiple congenital exostosis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 03, 2019

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminus of the EXT1 protein. Other variant(s) that disrupt this region (p.Trp711*) have been determined to be pathogenic (PMID: 29620724, Invitae). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. This variant has been reported in individuals affected with multiple osteochondromas (PMID: 19810120, Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the EXT1 gene (p.Gln702*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 45 amino acids of the EXT1 protein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
Cadd	Pathogenic	44
Dann	Uncertain	1.0
Eigen	Pathogenic	1.3
Eigen_PC	Pathogenic	1.2
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	D
Vest4		0.77
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.31		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.31		Position offset: 48

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1554656266; hg19: chr8-118812088;