rs11546829

Positions:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.00900

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 linkuse as main transcript	c.1065C>T	p.Cys355=	synonymous_variant	3/11	ENST00000378204.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
EXT1	ENST00000378204.7 linkuse as main transcript	c.1065C>T	p.Cys355=	synonymous_variant	3/11	1	NM_000127.3	P1
EXT1	ENST00000684189.1 linkuse as main transcript	n.532C>T		non_coding_transcript_exon_variant	3/11
EXT1	ENST00000436216.2 linkuse as main transcript	c.435C>T	p.Cys145=	synonymous_variant, NMD_transcript_variant	3/6	3
EXT1	ENST00000437196.1 linkuse as main transcript	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.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.281

AC XY:

203709

AN XY:

725840

show subpopulations

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.:

AF XY:

0.235

AC XY:

17467

AN XY:

74352

show subpopulations

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:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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	Labcorp Genetics (formerly Invitae), Labcorp	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	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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	- -

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over