rs17439693

Positions:

• chr8-117819781-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000127.3(EXT1):​c.1431C>T​(p.Pro477Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.188 in 1,611,950 control chromosomes in the GnomAD database, including 30,396 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. PS477L?) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.17 (2554 hom., cov: 32)
  • Exomes 𝑓: 0.19 (27842 hom.)
• Consequence: EXT1 NM_000127.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.248

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 8-117819781-G-A is Benign according to our data. Variant chr8-117819781-G-A is described in ClinVar as [Benign]. Clinvar id is 255172.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-117819781-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.248 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.203 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EXT1	NM_000127.3	c.1431C>T	p.Pro477Pro	synonymous_variant	6/11	ENST00000378204.7	NP_000118.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EXT1	ENST00000378204.7	c.1431C>T	p.Pro477Pro	synonymous_variant	6/11	1	NM_000127.3	ENSP00000367446.3
EXT1	ENST00000437196.1	n.*322C>T		non_coding_transcript_exon_variant	5/10	5		ENSP00000407299.1
EXT1	ENST00000684189.1	n.898C>T		non_coding_transcript_exon_variant	6/11
EXT1	ENST00000437196.1	n.*322C>T		3_prime_UTR_variant	5/10	5		ENSP00000407299.1

Frequencies

GnomAD3 genomes AF: 0.173 AC: 26232 AN: 151990 Hom.: 2556 Cov.: 32

Gnomad AFR AF: 0.102

Gnomad AMI AF: 0.206

Gnomad AMR AF: 0.192

Gnomad ASJ AF: 0.137

Gnomad EAS AF: 0.0383

Gnomad SAS AF: 0.122

Gnomad FIN AF: 0.305

Gnomad MID AF: 0.137

Gnomad NFE AF: 0.206

Gnomad OTH AF: 0.175

GnomAD3 exomes AF: 0.177 AC: 44336 AN: 250746 Hom.: 4491 AF XY: 0.176 AC XY: 23893 AN XY: 135560

Gnomad AFR exome AF: 0.103

Gnomad AMR exome AF: 0.182

Gnomad ASJ exome AF: 0.152

Gnomad EAS exome AF: 0.0360

Gnomad SAS exome AF: 0.118

Gnomad FIN exome AF: 0.307

Gnomad NFE exome AF: 0.201

Gnomad OTH exome AF: 0.190

GnomAD4 exome AF: 0.190 AC: 277351 AN: 1459842 Hom.: 27842 Cov.: 32 AF XY: 0.189 AC XY: 136972 AN XY: 726332

Gnomad4 AFR exome AF: 0.104

Gnomad4 AMR exome AF: 0.181

Gnomad4 ASJ exome AF: 0.150

Gnomad4 EAS exome AF: 0.0376

Gnomad4 SAS exome AF: 0.124

Gnomad4 FIN exome AF: 0.306

Gnomad4 NFE exome AF: 0.199

Gnomad4 OTH exome AF: 0.182

GnomAD4 genome AF: 0.173 AC: 26246 AN: 152108 Hom.: 2554 Cov.: 32 AF XY: 0.177 AC XY: 13142 AN XY: 74342

Gnomad4 AFR AF: 0.102

Gnomad4 AMR AF: 0.192

Gnomad4 ASJ AF: 0.137

Gnomad4 EAS AF: 0.0382

Gnomad4 SAS AF: 0.122

Gnomad4 FIN AF: 0.305

Gnomad4 NFE AF: 0.206

Gnomad4 OTH AF: 0.177

Alfa AF: 0.186 Hom.: 1929

Bravo AF: 0.162

Asia WGS AF: 0.100 AC: 349 AN: 3478

EpiCase AF: 0.198

EpiControl AF: 0.195

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple congenital exostosis Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Exostoses, multiple, type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	6.4
DANN	Benign	0.61

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: rs17439693; hg19: chr8-118832020;