8-117835543-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4BP6_Very_StrongBP7BA1

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

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.00900

Publications

23 publications found

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 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

EXT1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EXT1	NM_000127.3 link	c.1065C>T	p.Cys355Cys	synonymous_variant	Exon 3 of 11	ENST00000378204.7	NP_000118.2	Q16394

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
EXT1	ENST00000378204.7 link	c.1065C>T	p.Cys355Cys	synonymous_variant	Exon 3 of 11	1	NM_000127.3	ENSP00000367446.3	Q16394
EXT1	ENST00000436216.2 link	n.432C>T		non_coding_transcript_exon_variant	Exon 3 of 6	3		ENSP00000400372.1	H7C1H6
EXT1	ENST00000437196.1 link	n.82C>T		non_coding_transcript_exon_variant	Exon 2 of 10	5		ENSP00000407299.1	F8WF54
EXT1	ENST00000684189.1 link	n.532C>T		non_coding_transcript_exon_variant	Exon 3 of 11

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

GnomAD2 exomes

AF:

0.264

AC:

66198

AN:

250974

AF XY:

0.266

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 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

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

Heterozygous variant carriers

13825

27651

41476

55302

69127

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10644

21288

31932

42576

53220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.236

AC:

35937

AN:

152114

Hom.:

4733

Cov.:

AF XY:

0.235

AC XY:

17467

AN XY:

74352

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1365

2731

4096

5462

6827

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

368

736

1104

1472

1840

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Multiple congenital exostosis

Benign:3

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 05, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Exostoses, multiple, type 1

Benign:2

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_noAF

Benign

-0.39

CADD

Benign

7.8

(source)

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)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over