dbSNP rs188609829: EXT1:c.1633-26C>A (chr8-117812987-G-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000127.3(EXT1):c.1633-26C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0011 in 1,592,430 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0015 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 10 hom. )

Consequence

EXT1
NM_000127.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.548

Publications

2 publications found

Variant links:

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

EXT1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 8-117812987-G-T is Benign according to our data. Variant chr8-117812987-G-T is described in ClinVar as Benign. ClinVar VariationId is 255174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00146 (223/152264) while in subpopulation EAS AF = 0.0216 (112/5176). AF 95% confidence interval is 0.0184. There are 1 homozygotes in GnomAd4. There are 128 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 223 AD gene.

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.1633-26C>A		intron	N/A	NP_000118.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
EXT1	ENST00000378204.7	TSL:1 MANE Select	c.1633-26C>A	intron	N/A	ENSP00000367446.3	Q16394
EXT1	ENST00000437196.1	TSL:5	n.*524-26C>A	intron	N/A	ENSP00000407299.1	F8WF54
EXT1	ENST00000684189.1		n.1100-26C>A	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00147

AC:

223

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.0216

Gnomad SAS

AF:

0.00208

Gnomad FIN

AF:

0.00556

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000529

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00286

AC:

686

AN:

240176

AF XY:

0.00255

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0250

Gnomad FIN exome

AF:

0.00651

Gnomad NFE exome

AF:

0.000741

Gnomad OTH exome

AF:

0.00236

GnomAD4 exome

AF:

0.00106

AC:

1523

AN:

1440166

Hom.:

Cov.:

AF XY:

0.00105

AC XY:

753

AN XY:

717076

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33028

American (AMR)

AF:

0.00

AC:

AN:

43982

Ashkenazi Jewish (ASJ)

AF:

0.0000386

AC:

AN:

25910

East Asian (EAS)

AF:

0.0190

AC:

750

AN:

39406

South Asian (SAS)

AF:

0.000718

AC:

AN:

84924

European-Finnish (FIN)

AF:

0.00603

AC:

320

AN:

53042

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5726

European-Non Finnish (NFE)

AF:

0.000260

AC:

285

AN:

1094446

Other (OTH)

AF:

0.00178

AC:

106

AN:

59702

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

167

250

334

417

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00146

AC:

223

AN:

152264

Hom.:

Cov.:

AF XY:

0.00172

AC XY:

128

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41552

American (AMR)

AF:

0.000131

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.0216

AC:

112

AN:

5176

South Asian (SAS)

AF:

0.00208

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00556

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000529

AC:

AN:

68018

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000711

Hom.:

Bravo

AF:

0.00104

Asia WGS

AF:

0.00866

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Exostoses, multiple, type 1 (1)

Multiple congenital exostosis (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

5.5

(source)

DANN

Benign

0.74

PhyloP100

0.55

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over