chr11-44095859-G-T

Position:

• chr11-44095859-G-T

Variant summary

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

The NM_207122.2(EXT2):​c.-31+7G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.088 in 181,534 control chromosomes in the GnomAD database, including 847 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.088 (726 hom., cov: 34)
  • Exomes 𝑓: 0.087 (121 hom.)
• Consequence: EXT2 NM_207122.2 splice_region, intron
• Scores: Splicing: ADA: 0.01260
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.86

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 11-44095859-G-T is Benign according to our data. Variant chr11-44095859-G-T is described in ClinVar as [Benign]. Clinvar id is 304569.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-44095859-G-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.123 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EXT2	NM_207122.2	c.-31+7G>T		splice_region_variant, intron_variant		ENST00000533608.7	NP_997005.1
EXT2	NM_001178083.3	c.-31+7G>T		splice_region_variant, intron_variant			NP_001171554.1
EXT2	NM_001389630.1	c.-70+7G>T		splice_region_variant, intron_variant			NP_001376559.1
EXT2	XM_047426529.1	c.-183+7G>T		splice_region_variant, intron_variant			XP_047282485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EXT2	ENST00000533608.7	c.-31+7G>T		splice_region_variant, intron_variant		1	NM_207122.2	ENSP00000431173	P1

Frequencies

GnomAD3 genomes AF: 0.0882 AC: 13414 AN: 152112 Hom.: 725 Cov.: 34

Gnomad AFR AF: 0.126

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.0530

Gnomad ASJ AF: 0.0893

Gnomad EAS AF: 0.0162

Gnomad SAS AF: 0.130

Gnomad FIN AF: 0.0638

Gnomad MID AF: 0.0987

Gnomad NFE AF: 0.0805

Gnomad OTH AF: 0.0764

GnomAD4 exome AF: 0.0871 AC: 2552 AN: 29314 Hom.: 121 Cov.: 0 AF XY: 0.0890 AC XY: 1330 AN XY: 14946

Gnomad4 AFR exome AF: 0.147

Gnomad4 AMR exome AF: 0.0466

Gnomad4 ASJ exome AF: 0.103

Gnomad4 EAS exome AF: 0.0146

Gnomad4 SAS exome AF: 0.127

Gnomad4 FIN exome AF: 0.0818

Gnomad4 NFE exome AF: 0.0863

Gnomad4 OTH exome AF: 0.0762

GnomAD4 genome AF: 0.0882 AC: 13423 AN: 152220 Hom.: 726 Cov.: 34 AF XY: 0.0867 AC XY: 6455 AN XY: 74420

Gnomad4 AFR AF: 0.126

Gnomad4 AMR AF: 0.0529

Gnomad4 ASJ AF: 0.0893

Gnomad4 EAS AF: 0.0165

Gnomad4 SAS AF: 0.131

Gnomad4 FIN AF: 0.0638

Gnomad4 NFE AF: 0.0805

Gnomad4 OTH AF: 0.0756

Alfa AF: 0.0314 Hom.: 24

Bravo AF: 0.0861

Asia WGS AF: 0.0650 AC: 225 AN: 3464

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 09, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Jun 25, 2020

- -

Exostoses, multiple, type 2 Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	16
DANN	Benign	0.92
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.013
dbscSNV1_RF	Benign	0.030
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: rs58861092; hg19: chr11-44117409;