NM_207122.2:c.-30-10T>A

Variant names:

• chr11-44107673-T-A
• rs371744028
• NM_207122.2:c.-30-10T>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_207122.2(EXT2):​c.-30-10T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000312 in 1,600,380 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: EXT2 NM_207122.2 intron
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: -0.655

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EXT2	NM_207122.2	c.-30-10T>A		intron_variant	Intron 1 of 13	ENST00000533608.7	NP_997005.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EXT2	ENST00000533608.7	c.-30-10T>A		intron_variant	Intron 1 of 13	1	NM_207122.2	ENSP00000431173.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152236 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000809 AC: 2 AN: 247308 Hom.: 0 AF XY: 0.00000749 AC XY: 1 AN XY: 133484

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000276 AC: 4 AN: 1448144 Hom.: 0 Cov.: 31 AF XY: 0.00000279 AC XY: 2 AN XY: 717724

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000363

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152236 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74366

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Multiple congenital exostosis Uncertain:1

Mar 17, 2022

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The EXT2 c.70-10T>A intronic change results from a T to A substitution at the -10 position of intron 1 of the EXT2 gene. Algorithms that predict the impact of sequence changes on splicing indicate that this change may result in loss of the native acceptor site at c.70 and gain of a new acceptor site at c.70-8 (PP3). RNA data also demonstrate the creation of a new acceptor site that may result in premature protein truncation (internal data). This variant has a maximum subpopulation frequency of 0.0018% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/11-44129223-T-A?dataset=gnomad_r2_1). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PP3. -

EXT2-related disorder Uncertain:1

Aug 21, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The EXT2 c.70-10T>A variant is predicted to interfere with splicing. This variant is predicted to create a cryptic splice site based on available splicing prediction programs (SpliceAI, Jaganathan et al. 2019. PubMed ID: 30661751), however, such computer prediction programs are imperfect. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is classified as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/1691544/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	20
DANN	Benign	0.77

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		1.0		Position offset: 2
DS_AL_spliceai		0.97		Position offset: 10

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs371744028; hg19: chr11-44129223;