Genetic Variant NM_000127.3:c.1761G>A (chr8-117807339-C-T) – ACMG Classification: Benign (-18 pts)

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 4.06

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 -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 id is 255175.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-117807339-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.496 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EXT1	NM_000127.3 link	c.1761G>A	p.Glu587Glu	synonymous_variant	Exon 9 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.1761G>A	p.Glu587Glu	synonymous_variant	Exon 9 of 11	1	NM_000127.3	ENSP00000367446.3	Q16394
EXT1	ENST00000437196.1 link	n.*652G>A		non_coding_transcript_exon_variant	Exon 8 of 10	5		ENSP00000407299.1	F8WF54
EXT1	ENST00000684189.1 link	n.1228G>A		non_coding_transcript_exon_variant	Exon 9 of 11
EXT1	ENST00000437196.1 link	n.*652G>A		3_prime_UTR_variant	Exon 8 of 10	5		ENSP00000407299.1	F8WF54

Frequencies

GnomAD3 genomes

AF:

0.364

AC:

55244

AN:

151924

Hom.:

10799

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.407

AC:

102306

AN:

251290

Hom.:

21778

AF XY:

0.405

AC XY:

55000

AN XY:

135812

show subpopulations

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 SAS exome

AF:

0.341

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.:

AF XY:

0.401

AC XY:

291864

AN XY:

727192

show subpopulations

Gnomad4 AFR exome

AF:

0.204

Gnomad4 AMR exome

AF:

0.534

Gnomad4 ASJ exome

AF:

0.400

Gnomad4 EAS exome

AF:

0.310

Gnomad4 SAS exome

AF:

0.348

Gnomad4 FIN exome

AF:

0.424

Gnomad4 NFE exome

AF:

0.410

Gnomad4 OTH exome

AF:

0.405

GnomAD4 genome

AF:

0.364

AC:

55270

AN:

152042

Hom.:

10803

Cov.:

AF XY:

0.366

AC XY:

27193

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.209

Gnomad4 AMR

AF:

0.506

Gnomad4 ASJ

AF:

0.407

Gnomad4 EAS

AF:

0.372

Gnomad4 SAS

AF:

0.338

Gnomad4 FIN

AF:

0.418

Gnomad4 NFE

AF:

0.415

Gnomad4 OTH

AF:

0.426

Alfa

AF:

0.407

Hom.:

26105

Bravo

AF:

0.368

Asia WGS

AF:

0.319

AC:

1111

AN:

3478

EpiCase

AF:

0.428

EpiControl

AF:

0.435

ClinVar

Significance: Benign

Submissions summary: Benign:7

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

- -

Aug 10, 2021

Genome-Nilou Lab

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. -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Exostoses, multiple, type 1

Benign:1

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

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Benign

0.53

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

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