rs1554601481

chr8-118110200-AG-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000127.3(EXT1):c.846del(p.Leu283TyrfsTer76) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EXT1 NM_000127.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.27

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 12 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 8-118110200-AG-A is Pathogenic according to our data. Variant chr8-118110200-AG-A is described in ClinVar as [Pathogenic]. Clinvar id is 526306.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EXT1	NM_000127.3	c.846del	p.Leu283TyrfsTer76	frameshift_variant	1/11	ENST00000378204.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EXT1	ENST00000378204.7	c.846del	p.Leu283TyrfsTer76	frameshift_variant	1/11	1	NM_000127.3	P1
EXT1	ENST00000436216.2	c.214del	p.Leu73TyrfsTer76	frameshift_variant, NMD_transcript_variant	1/6	3
EXT1	ENST00000437196.1	c.73+773del		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:1

Revision: criteria provided, single submitter

Submissions by phenotype

Multiple congenital exostosis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 04, 2017

Loss-of-function variants in EXT1 are known to be pathogenic (PMID: 10679937, 11391482, 19810120). This variant has not been reported in the literature in individuals with EXT1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Leu283Tyrfs*76) in the EXT1 gene. It is expected to result in an absent or disrupted protein product. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

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: rs1554601481; hg19: chr8-119122439;