11-44096326-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000343631.4(EXT2):c.-31+5G>A variant causes a splice donor 5th base, 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 ENST00000343631.4 splice_donor_5th_base, intron
• Scores: Splicing: ADA: 0.9939
• Clinical Significance: Likely benign criteria provided, single submitter B:3
• Conservation: PhyloP100: 0.802

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]

ACMG classification

Verdict is Benign. Variant got -14 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_single_submitter, 1 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 GnomAd at 3297 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EXT2	NM_207122.2	c.-31+474G>A		intron_variant		ENST00000533608.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EXT2	ENST00000533608.7	c.-31+474G>A		intron_variant		1	NM_207122.2	P1

Frequencies

GnomAD3 genomes AF: 0.0217 AC: 3297 AN: 152152 Hom.: 50 Cov.: 32

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.: 36 AF XY: 0.0207 AC XY: 1531 AN XY: 74082

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.: 32 AF XY: 0.0279 AC XY: 19020 AN XY: 682722

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.: 50 Cov.: 32 AF XY: 0.0211 AC XY: 1574 AN XY: 74454

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.: 16

Bravo AF: 0.0202

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 06, 2019	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, Amsterdam University Medical Center

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
Cadd	Benign	14
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

Other links and lift over

dbSNP: rs112082531; hg19: chr11-44117876; COSMIC: COSV59154467;