rs1554580147

Variant names:

• chr8-117837128-T-C
• rs1554580147
• NM_000127.3:c.1036A>G

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000127.3(EXT1):​c.1036A>G​(p.Arg346Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R346K) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EXT1 NM_000127.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 5.53
• Publications: 1 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: Pathogenic. The variant received 18 ACMG points.

• PM1: In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000127.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-117837127-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3659932.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 8-117837128-T-C is Pathogenic according to our data. Variant chr8-117837128-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 526301.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.1036A>G	p.Arg346Gly	missense	Exon 2 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.1036A>G	p.Arg346Gly	missense	Exon 2 of 11	ENSP00000367446.3
	EXT1	ENST00000436216.2	TSL:3	n.403A>G		non_coding_transcript_exon	Exon 2 of 6	ENSP00000400372.1
	EXT1	ENST00000684189.1		n.503A>G		non_coding_transcript_exon	Exon 2 of 11

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Multiple congenital exostosis (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	H
PhyloP100		5.5
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.7	D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.010	D
Polyphen		0.94	P
Vest4		0.97
MutPred		0.90		Loss of methylation at R346 (P = 0.0585)
MVP		1.0
MPC		1.3
ClinPred		1.0	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.67
gMVP		0.97
Mutation Taster		=5/95	disease causing (ClinVar)

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: rs1554580147; hg19: chr8-118849367;