10-72007522-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1PM2PP3_StrongPP5_Moderate

The NM_004273.5(CHST3):c.491C>T(p.Pro164Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000276 in 1,451,634 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. P164P) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

CHST3
NM_004273.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.84

Publications

4 publications found

Variant links:

Genes affected

CHST3 (HGNC:1971): (carbohydrate sulfotransferase 3) This gene encodes an enzyme which catalyzes the sulfation of chondroitin, a proteoglycan found in the extracellular matrix and most cells which is involved in cell migration and differentiation. Mutations in this gene are associated with spondylepiphyseal dysplasia and humerospinal dysostosis. [provided by RefSeq, Mar 2009]

CHST3 Gene-Disease associations (from GenCC):

spondyloepiphyseal dysplasia with congenital joint dislocations
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P

CHST3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_004273.5

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.992

PP5

Variant 10-72007522-C-T is Pathogenic according to our data. Variant chr10-72007522-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 478823.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHST3	NM_004273.5 link	c.491C>T	p.Pro164Leu	missense_variant	Exon 3 of 3	ENST00000373115.5	NP_004264.2	Q7LGC8
CHST3	NM_001441201.1 link	c.491C>T	p.Pro164Leu	missense_variant	Exon 3 of 3		NP_001428130.1
CHST3	NM_001441202.1 link	c.491C>T	p.Pro164Leu	missense_variant	Exon 3 of 3		NP_001428131.1
CHST3	XM_011540369.3 link	c.491C>T	p.Pro164Leu	missense_variant	Exon 3 of 3		XP_011538671.1	Q7LGC8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHST3	ENST00000373115.5 link	c.491C>T	p.Pro164Leu	missense_variant	Exon 3 of 3	1	NM_004273.5	ENSP00000362207.4		Q7LGC8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000423

AC:

AN:

236198

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000276

AC:

AN:

1451634

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

722542

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33466

American (AMR)

AF:

0.00

AC:

AN:

44678

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26094

East Asian (EAS)

AF:

0.00

AC:

AN:

39678

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86200

European-Finnish (FIN)

AF:

0.00

AC:

AN:

43718

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111762

Other (OTH)

AF:

0.00

AC:

AN:

60272

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000344

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Spondyloepiphyseal dysplasia with congenital joint dislocations

Pathogenic:1

Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant was found to be pathogenic by various in silico tools, including MutationTaster, SIFT, and PolyPhen. Parents were found to be carriers. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.87

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.90

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.96

M_CAP

Uncertain

0.23

MetaRNN

Pathogenic

0.99

MetaSVM

Uncertain

0.67

MutationAssessor

Pathogenic

3.3

PhyloP100

7.8

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-10

REVEL

Pathogenic

0.87

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.97

MutPred

0.96

Loss of catalytic residue at L161 (P = 0.2472);

MVP

0.97

MPC

1.7

ClinPred

1.0

GERP RS

5.7

Varity_R

0.97

gMVP

0.95

Mutation Taster

=8/92

disease causing (ClinVar)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over