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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000127.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EXT1	NM_000127.3	MANE Select	c.1431C>T	p.Pro477Pro	synonymous	Exon 6 of 11	NP_000118.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EXT1	ENST00000378204.7	TSL:1 MANE Select	c.1431C>T	p.Pro477Pro	synonymous	Exon 6 of 11	ENSP00000367446.3	Q16394
	EXT1	ENST00000437196.1	TSL:5	n.*322C>T		non_coding_transcript_exon	Exon 5 of 10	ENSP00000407299.1	F8WF54
	EXT1	ENST00000684189.1		n.898C>T		non_coding_transcript_exon	Exon 6 of 11

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Multiple congenital exostosis (2)
-	-	2	not provided (2)
-	-	1	Exostoses, multiple, type 1 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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;