rs1554601502

Variant names:

• chr8-118110377-CAGTACTGATGCTGGCTTTGGCCAGCATCGCCTGGCCGATGTCAAACCCCACGTCCTCGGTGTAGTCAGGCCA-C
• rs1554601502
• NM_000127.3:c.598_669delTGGCCTGACTACACCGAGGACGTGGGGTTTGACATCGGCCAGGCGATGCTGGCCAAAGCCAGCATCAGTACT

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM4 PP3 PP5_Moderate

The NM_000127.3(EXT1):​c.598_669delTGGCCTGACTACACCGAGGACGTGGGGTTTGACATCGGCCAGGCGATGCTGGCCAAAGCCAGCATCAGTACT​(p.Trp200_Thr223del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EXT1 NM_000127.3 conservative_inframe_deletion
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.24
• 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_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000127.3
• PM4: Nonframeshift variant in NON repetitive region in NM_000127.3.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 8-118110377-CAGTACTGATGCTGGCTTTGGCCAGCATCGCCTGGCCGATGTCAAACCCCACGTCCTCGGTGTAGTCAGGCCA-C is Pathogenic according to our data. Variant chr8-118110377-CAGTACTGATGCTGGCTTTGGCCAGCATCGCCTGGCCGATGTCAAACCCCACGTCCTCGGTGTAGTCAGGCCA-C is described in ClinVar as Pathogenic. ClinVar VariationId is 456064.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000127.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EXT1	NM_000127.3	MANE Select	c.598_669delTGGCCTGACTACACCGAGGACGTGGGGTTTGACATCGGCCAGGCGATGCTGGCCAAAGCCAGCATCAGTACT	p.Trp200_Thr223del	conservative_inframe_deletion	Exon 1 of 11	NP_000118.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EXT1	ENST00000378204.7	TSL:1 MANE Select	c.598_669delTGGCCTGACTACACCGAGGACGTGGGGTTTGACATCGGCCAGGCGATGCTGGCCAAAGCCAGCATCAGTACT	p.Trp200_Thr223del	conservative_inframe_deletion	Exon 1 of 11	ENSP00000367446.3	Q16394
	EXT1	ENST00000436216.2	TSL:3	n.-36_36delTGGCCTGACTACACCGAGGACGTGGGGTTTGACATCGGCCAGGCGATGCTGGCCAAAGCCAGCATCAGTACT		5_prime_UTR_truncation exon_loss	Exon 1 of 6	ENSP00000400372.1	H7C1H6
	EXT1	ENST00000436216.2	TSL:3	n.-36_36delTGGCCTGACTACACCGAGGACGTGGGGTTTGACATCGGCCAGGCGATGCTGGCCAAAGCCAGCATCAGTACT		non_coding_transcript_exon	Exon 1 of 6	ENSP00000400372.1	H7C1H6

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Multiple congenital exostosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.2
Mutation Taster		=4/196	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1554601502; hg19: chr8-119122616;