rs7837891

chr8-117807339-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_000127.3(EXT1):c.1761G>A(p.Glu587=) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 4.06

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 -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/exons	MANE	UniProt
EXT1	NM_000127.3	c.1761G>A	p.Glu587=	synonymous_variant	9/11	ENST00000378204.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EXT1	ENST00000378204.7	c.1761G>A	p.Glu587=	synonymous_variant	9/11	1	NM_000127.3	P1
EXT1	ENST00000684189.1	n.1228G>A		non_coding_transcript_exon_variant	9/11
EXT1	ENST00000437196.1	c.*652G>A		3_prime_UTR_variant, NMD_transcript_variant	8/10	5

Frequencies

GnomAD3 genomes AF: 0.364 AC: 55244 AN: 151924 Hom.: 10799 Cov.: 32

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

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.: 55 AF XY: 0.401 AC XY: 291864 AN XY: 727192

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.: 32 AF XY: 0.366 AC XY: 27193 AN XY: 74314

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:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple congenital exostosis Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
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. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Exostoses, multiple, type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
Cadd	Benign	11
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

Other links and lift over

dbSNP: rs7837891; hg19: chr8-118819578; COSMIC: COSV65476711;