rs17439693

Variant names:

• chr8-117819781-G-A
• rs17439693
• NM_000127.3:c.1431C>T

Variant summary

Our verdict is Benign. The variant received -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 (★★).

• 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
• Publications: 20 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: Benign. The variant received -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 VariationId is 255172.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
EXT1	NM_000127.3	c.1431C>T	p.Pro477Pro	synonymous_variant	Exon 6 of 11	ENST00000378204.7	NP_000118.2

Ensembl

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

GnomAD2 exomes AF: 0.177 AC: 44336 AN: 250746 AF XY: 0.176

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 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

African (AFR) AF: 0.104 AC: 3473 AN: 33442

American (AMR) AF: 0.181 AC: 8109 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.150 AC: 3910 AN: 26128

East Asian (EAS) AF: 0.0376 AC: 1494 AN: 39700

South Asian (SAS) AF: 0.124 AC: 10665 AN: 86212

European-Finnish (FIN) AF: 0.306 AC: 16335 AN: 53400

Middle Eastern (MID) AF: 0.172 AC: 896 AN: 5218

European-Non Finnish (NFE) AF: 0.199 AC: 221483 AN: 1110730

Other (OTH) AF: 0.182 AC: 10986 AN: 60300

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

African (AFR) AF: 0.102 AC: 4249 AN: 41536

American (AMR) AF: 0.192 AC: 2933 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.137 AC: 477 AN: 3470

East Asian (EAS) AF: 0.0382 AC: 198 AN: 5180

South Asian (SAS) AF: 0.122 AC: 586 AN: 4810

European-Finnish (FIN) AF: 0.305 AC: 3223 AN: 10554

Middle Eastern (MID) AF: 0.137 AC: 40 AN: 292

European-Non Finnish (NFE) AF: 0.206 AC: 13977 AN: 67958

Other (OTH) AF: 0.177 AC: 375 AN: 2114

Alfa AF: 0.184 Hom.: 6076

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

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Exostoses, multiple, type 1 Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	6.4
DANN	Benign	0.61
PhyloP100		-0.25
Mutation Taster		=100/0	polymorphism (auto)

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: rs17439693; hg19: chr8-118832020; COSMIC: COSV108236613;