Genetic Variant EXT2:c.-31+474G>A (chr11-44096326-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000401.3(EXT2):c.69+5G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0277 in 1,535,772 control chromosomes in the GnomAD database, including 713 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.022 ( 50 hom., cov: 32)

Exomes 𝑓: 0.028 ( 663 hom. )

Consequence

EXT2
NM_000401.3 splice_region, intron

Scores

Splicing: ADA: 0.9939

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.802

Variant links:

Genes affected

EXT2 (HGNC:3513): (exostosin glycosyltransferase 2) This gene encodes one of two glycosyltransferases involved in the chain elongation step of heparan sulfate biosynthesis. Mutations in this gene cause the type II form of multiple exostoses. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Jul 2008]

EXT2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.58).

BP6

Variant 11-44096326-G-A is Benign according to our data. Variant chr11-44096326-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1182129.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-44096326-G-A is described in Lovd as [Benign]. Variant chr11-44096326-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0217 (3300/152270) while in subpopulation NFE AF= 0.0322 (2189/68010). AF 95% confidence interval is 0.0311. There are 50 homozygotes in gnomad4. There are 1574 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 3300 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EXT2	NM_207122.2 link	c.-31+474G>A		intron_variant	Intron 1 of 13	ENST00000533608.7	NP_997005.1	Q93063-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EXT2	ENST00000533608.7 link	c.-31+474G>A		intron_variant	Intron 1 of 13	1	NM_207122.2	ENSP00000431173.2		Q93063-1

Frequencies

GnomAD3 genomes

AF:

0.0217

AC:

3297

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00671

Gnomad AMI

AF:

0.0526

Gnomad AMR

AF:

0.0167

Gnomad ASJ

AF:

0.0242

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00518

Gnomad FIN

AF:

0.0339

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0322

Gnomad OTH

AF:

0.0249

GnomAD3 exomes

AF:

0.0205

AC:

2801

AN:

136450

Hom.:

AF XY:

0.0207

AC XY:

1531

AN XY:

74082

show subpopulations

Gnomad AFR exome

AF:

0.00621

Gnomad AMR exome

AF:

0.0133

Gnomad ASJ exome

AF:

0.0209

Gnomad EAS exome

AF:

0.0000951

Gnomad SAS exome

AF:

0.00832

Gnomad FIN exome

AF:

0.0355

Gnomad NFE exome

AF:

0.0326

Gnomad OTH exome

AF:

0.0235

GnomAD4 exome

AF:

0.0283

AC:

39167

AN:

1383502

Hom.:

663

Cov.:

AF XY:

0.0279

AC XY:

19020

AN XY:

682722

show subpopulations

Gnomad4 AFR exome

AF:

0.00674

Gnomad4 AMR exome

AF:

0.0138

Gnomad4 ASJ exome

AF:

0.0207

Gnomad4 EAS exome

AF:

0.0000280

Gnomad4 SAS exome

AF:

0.00779

Gnomad4 FIN exome

AF:

0.0329

Gnomad4 NFE exome

AF:

0.0319

Gnomad4 OTH exome

AF:

0.0283

GnomAD4 genome

AF:

0.0217

AC:

3300

AN:

152270

Hom.:

Cov.:

AF XY:

0.0211

AC XY:

1574

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.00674

Gnomad4 AMR

AF:

0.0167

Gnomad4 ASJ

AF:

0.0242

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00539

Gnomad4 FIN

AF:

0.0339

Gnomad4 NFE

AF:

0.0322

Gnomad4 OTH

AF:

0.0246

Alfa

AF:

0.0264

Hom.:

Bravo

AF:

0.0202

Asia WGS

AF:

0.00289

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Sep 06, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.58

CADD

Benign

DANN

Benign

0.90

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Benign

0.70

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