rs11546829

chr8-117835543-G-Achr8-117835543-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000127.3(EXT1):c.1065C>T(p.Cys355=) 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:8
• Conservation: PhyloP100: -0.00900

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 8-117835543-G-A is Benign according to our data. Variant chr8-117835543-G-A is described in ClinVar as [Benign]. Clinvar id is 196215.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-117835543-G-A is described in Lovd as [Benign].
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EXT1	NM_000127.3	c.1065C>T	p.Cys355=	synonymous_variant	3/11	ENST00000378204.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EXT1	ENST00000378204.7	c.1065C>T	p.Cys355=	synonymous_variant	3/11	1	NM_000127.3	P1
EXT1	ENST00000684189.1	n.532C>T		non_coding_transcript_exon_variant	3/11
EXT1	ENST00000436216.2	c.435C>T	p.Cys145=	synonymous_variant, NMD_transcript_variant	3/6	3
EXT1	ENST00000437196.1	c.82C>T	p.Arg28Cys	missense_variant, NMD_transcript_variant	2/10	5

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

GnomAD3 exomes AF: 0.264 AC: 66198 AN: 250974 Hom.: 9490 AF XY: 0.266 AC XY: 36077 AN XY: 135608

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 SAS exome AF: 0.248

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

Gnomad4 AFR exome AF: 0.119

Gnomad4 AMR exome AF: 0.331

Gnomad4 ASJ exome AF: 0.296

Gnomad4 EAS exome AF: 0.0892

Gnomad4 SAS exome AF: 0.249

Gnomad4 FIN exome AF: 0.247

Gnomad4 NFE exome AF: 0.295

Gnomad4 OTH exome AF: 0.274

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

Gnomad4 AFR AF: 0.128

Gnomad4 AMR AF: 0.302

Gnomad4 ASJ AF: 0.309

Gnomad4 EAS AF: 0.0855

Gnomad4 SAS AF: 0.217

Gnomad4 FIN AF: 0.251

Gnomad4 NFE AF: 0.293

Gnomad4 OTH AF: 0.272

Alfa AF: 0.275 Hom.: 4002

Bravo AF: 0.237

Asia WGS AF: 0.157 AC: 548 AN: 3478

EpiCase AF: 0.311

EpiControl AF: 0.312

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple congenital exostosis Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 05, 2014	- -

Exostoses, multiple, type 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
Cadd	Benign	7.8
Dann	Benign	0.86
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs11546829; hg19: chr8-118847782; COSMIC: COSV65475754;