8-117799754-G-A

Variant names:

• chr8-117799754-G-A
• rs201230140
• NM_000127.3:c.2199C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Moderate BP6_Moderate BP7

The NM_000127.3(EXT1):​c.2199C>T​(p.Val733Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. V733V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EXT1 NM_000127.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.00
• Publications: 0 publications found

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]

EXT1 Gene-Disease associations (from GenCC):

• exostoses, multiple, type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen
• chondrosarcoma

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• hereditary multiple osteochondromas

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 8-117799754-G-A is Benign according to our data. Variant chr8-117799754-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1103572.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=3 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EXT1	NM_000127.3	c.2199C>T	p.Val733Val	synonymous_variant	Exon 11 of 11	ENST00000378204.7	NP_000118.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EXT1	ENST00000378204.7	c.2199C>T	p.Val733Val	synonymous_variant	Exon 11 of 11	1	NM_000127.3	ENSP00000367446.3
EXT1	ENST00000684189.1	n.1666C>T		non_coding_transcript_exon_variant	Exon 11 of 11
EXT1	ENST00000684443.1	n.2325C>T		non_coding_transcript_exon_variant	Exon 2 of 2
EXT1	ENST00000437196.1	n.*1090C>T		downstream_gene_variant		5		ENSP00000407299.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Multiple congenital exostosis Benign:1

Feb 03, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	11
DANN	Benign	0.78
PhyloP100		3.0

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

Other links and lift over

dbSNP: rs201230140; hg19: chr8-118811993; COSMIC: COSV65479395; COSMIC: COSV65479395;