rs1554657437

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000127.3(EXT1):​c.1810G>T​(p.Glu604*) 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)

Consequence

EXT1
NM_000127.3 stop_gained

Scores

4
2
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 6.07
Variant links:
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]

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ACMG classification

Classification made for transcript

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 8-117807290-C-A is Pathogenic according to our data. Variant chr8-117807290-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 488827.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-117807290-C-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
EXT1NM_000127.3 linkc.1810G>T p.Glu604* stop_gained 9/11 ENST00000378204.7 NP_000118.2 Q16394

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
EXT1ENST00000378204.7 linkc.1810G>T p.Glu604* stop_gained 9/111 NM_000127.3 ENSP00000367446.3 Q16394
EXT1ENST00000437196.1 linkn.*701G>T non_coding_transcript_exon_variant 8/105 ENSP00000407299.1 F8WF54
EXT1ENST00000684189.1 linkn.1277G>T non_coding_transcript_exon_variant 9/11
EXT1ENST00000437196.1 linkn.*701G>T 3_prime_UTR_variant 8/105 ENSP00000407299.1 F8WF54

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Multiple congenital exostosis Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpApr 14, 2018This variant has been reported in an individual affected with multiple osteochondromas (PMID: 18165274). ClinVar contains an entry for this variant (Variation ID: 488827). For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in EXT1 are known to be pathogenic (PMID: 10679937, 11391482, 19810120). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Glu604*) in the EXT1 gene. It is expected to result in an absent or disrupted protein product. -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGeneDxJan 02, 2018The E604X variant in the EXT1 gene has been reported previously in at least one individual with multiple exostoses (Jennes et al., 2008). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The E604X variant is not observed in large population cohorts (Lek et al., 2016). We interpret E604X as a pathogenic variant . -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.58
CADD
Pathogenic
46
DANN
Uncertain
1.0
Eigen
Pathogenic
0.91
Eigen_PC
Pathogenic
0.79
FATHMM_MKL
Uncertain
0.95
D
Vest4
0.96
GERP RS
5.1

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1554657437; hg19: chr8-118819529; API