rs11546829

Variant names:

• chr8-117835543-G-A
• rs11546829
• NM_000127.3:c.1065C>T

Your query was ambiguous. Multiple possible variants found:

• chr8-117835543-G-A
• chr8-117835543-G-T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4 BP6_Very_Strong BP7 BA1

The NM_000127.3(EXT1):​c.1065C>T​(p.Cys355Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.277 in 1,610,886 control chromosomes in the GnomAD database, including 64,666 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (4733 hom., cov: 32)
  • Exomes 𝑓: 0.28 (59933 hom.)
• Consequence: EXT1 NM_000127.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.00900
• Publications: 23 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 (REVEL=0.286).
• BP6: Variant 8-117835543-G-A is Benign according to our data. Variant chr8-117835543-G-A is described in ClinVar as Benign. ClinVar VariationId is 196215.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.009 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.294 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.1065C>T	p.Cys355Cys	synonymous	Exon 3 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.1065C>T	p.Cys355Cys	synonymous	Exon 3 of 11	ENSP00000367446.3
	EXT1	ENST00000436216.2	TSL:3	n.432C>T		non_coding_transcript_exon	Exon 3 of 6	ENSP00000400372.1
	EXT1	ENST00000437196.1	TSL:5	n.82C>T		non_coding_transcript_exon	Exon 2 of 10	ENSP00000407299.1

Frequencies

GnomAD3 genomes AF: 0.236 AC: 35927 AN: 151996 Hom.: 4728 Cov.: 32

Gnomad AFR AF: 0.128

Gnomad AMI AF: 0.252

Gnomad AMR AF: 0.301

Gnomad ASJ AF: 0.309

Gnomad EAS AF: 0.0855

Gnomad SAS AF: 0.217

Gnomad FIN AF: 0.251

Gnomad MID AF: 0.386

Gnomad NFE AF: 0.293

Gnomad OTH AF: 0.273

GnomAD2 exomes AF: 0.264 AC: 66198 AN: 250974 AF XY: 0.266

Gnomad AFR exome AF: 0.121

Gnomad AMR exome AF: 0.334

Gnomad ASJ exome AF: 0.294

Gnomad EAS exome AF: 0.0805

Gnomad FIN exome AF: 0.246

Gnomad NFE exome AF: 0.296

Gnomad OTH exome AF: 0.290

GnomAD4 exome AF: 0.281 AC: 410007 AN: 1458772 Hom.: 59933 Cov.: 33 AF XY: 0.281 AC XY: 203709 AN XY: 725840

African (AFR) AF: 0.119 AC: 3964 AN: 33448

American (AMR) AF: 0.331 AC: 14797 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.296 AC: 7740 AN: 26120

East Asian (EAS) AF: 0.0892 AC: 3539 AN: 39688

South Asian (SAS) AF: 0.249 AC: 21438 AN: 86212

European-Finnish (FIN) AF: 0.247 AC: 13201 AN: 53412

Middle Eastern (MID) AF: 0.327 AC: 1882 AN: 5762

European-Non Finnish (NFE) AF: 0.295 AC: 326937 AN: 1109160

Other (OTH) AF: 0.274 AC: 16509 AN: 60258

GnomAD4 genome AF: 0.236 AC: 35937 AN: 152114 Hom.: 4733 Cov.: 32 AF XY: 0.235 AC XY: 17467 AN XY: 74352

African (AFR) AF: 0.128 AC: 5307 AN: 41518

American (AMR) AF: 0.302 AC: 4611 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.309 AC: 1071 AN: 3468

East Asian (EAS) AF: 0.0855 AC: 442 AN: 5170

South Asian (SAS) AF: 0.217 AC: 1046 AN: 4812

European-Finnish (FIN) AF: 0.251 AC: 2658 AN: 10570

Middle Eastern (MID) AF: 0.384 AC: 113 AN: 294

European-Non Finnish (NFE) AF: 0.293 AC: 19885 AN: 67970

Other (OTH) AF: 0.272 AC: 574 AN: 2112

Alfa AF: 0.273 Hom.: 5229

Bravo AF: 0.237

Asia WGS AF: 0.157 AC: 548 AN: 3478

EpiCase AF: 0.311

EpiControl AF: 0.312

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Multiple congenital exostosis (3)
-	-	2	Exostoses, multiple, type 1 (2)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_noAF	Benign	-0.39
CADD	Benign	7.8
DANN	Benign	0.86
PhyloP100		-0.0090
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=85/15	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs11546829; hg19: chr8-118847782; COSMIC: COSV65475754;