rs7837891

Variant names:

• chr8-117807339-C-T
• rs7837891
• NM_000127.3:c.1761G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_000127.3(EXT1):​c.1761G>A​(p.Glu587Glu) variant causes a synonymous change. The variant allele was found at a frequency of 0.399 in 1,613,820 control chromosomes in the GnomAD database, including 131,429 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (10803 hom., cov: 32)
  • Exomes 𝑓: 0.40 (120626 hom.)
• Consequence: EXT1 NM_000127.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 4.06
• Publications: 28 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 8-117807339-C-T is Benign according to our data. Variant chr8-117807339-C-T is described in ClinVar as Benign. ClinVar VariationId is 255175.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.496 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.1761G>A	p.Glu587Glu	synonymous	Exon 9 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.1761G>A	p.Glu587Glu	synonymous	Exon 9 of 11	ENSP00000367446.3
	EXT1	ENST00000437196.1	TSL:5	n.*652G>A		non_coding_transcript_exon	Exon 8 of 10	ENSP00000407299.1
	EXT1	ENST00000684189.1		n.1228G>A		non_coding_transcript_exon	Exon 9 of 11

Frequencies

GnomAD3 genomes AF: 0.364 AC: 55244 AN: 151924 Hom.: 10799 Cov.: 32

Gnomad AFR AF: 0.209

Gnomad AMI AF: 0.311

Gnomad AMR AF: 0.506

Gnomad ASJ AF: 0.407

Gnomad EAS AF: 0.372

Gnomad SAS AF: 0.338

Gnomad FIN AF: 0.418

Gnomad MID AF: 0.440

Gnomad NFE AF: 0.415

Gnomad OTH AF: 0.425

GnomAD2 exomes AF: 0.407 AC: 102306 AN: 251290 AF XY: 0.405

Gnomad AFR exome AF: 0.206

Gnomad AMR exome AF: 0.536

Gnomad ASJ exome AF: 0.398

Gnomad EAS exome AF: 0.371

Gnomad FIN exome AF: 0.420

Gnomad NFE exome AF: 0.417

Gnomad OTH exome AF: 0.429

GnomAD4 exome AF: 0.403 AC: 588778 AN: 1461778 Hom.: 120626 Cov.: 55 AF XY: 0.401 AC XY: 291864 AN XY: 727192

African (AFR) AF: 0.204 AC: 6820 AN: 33480

American (AMR) AF: 0.534 AC: 23879 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.400 AC: 10455 AN: 26136

East Asian (EAS) AF: 0.310 AC: 12302 AN: 39700

South Asian (SAS) AF: 0.348 AC: 30049 AN: 86258

European-Finnish (FIN) AF: 0.424 AC: 22666 AN: 53406

Middle Eastern (MID) AF: 0.470 AC: 2708 AN: 5766

European-Non Finnish (NFE) AF: 0.410 AC: 455472 AN: 1111928

Other (OTH) AF: 0.405 AC: 24427 AN: 60388

GnomAD4 genome AF: 0.364 AC: 55270 AN: 152042 Hom.: 10803 Cov.: 32 AF XY: 0.366 AC XY: 27193 AN XY: 74314

African (AFR) AF: 0.209 AC: 8658 AN: 41498

American (AMR) AF: 0.506 AC: 7715 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.407 AC: 1411 AN: 3468

East Asian (EAS) AF: 0.372 AC: 1914 AN: 5146

South Asian (SAS) AF: 0.338 AC: 1628 AN: 4822

European-Finnish (FIN) AF: 0.418 AC: 4411 AN: 10554

Middle Eastern (MID) AF: 0.449 AC: 132 AN: 294

European-Non Finnish (NFE) AF: 0.415 AC: 28221 AN: 67984

Other (OTH) AF: 0.426 AC: 896 AN: 2102

Alfa AF: 0.398 Hom.: 38209

Bravo AF: 0.368

Asia WGS AF: 0.319 AC: 1111 AN: 3478

EpiCase AF: 0.428

EpiControl AF: 0.435

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Multiple congenital exostosis (3)
-	-	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	-0.39
CADD	Benign	11
DANN	Benign	0.53
PhyloP100		4.1
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: rs7837891; hg19: chr8-118819578; COSMIC: COSV65476711;