Genetic Variant CHST3:p.Arg222Trp (chr10-72007695-C-T) – ACMG Classification: Likely_pathogenic (9 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5

The NM_004273.5(CHST3):c.664C>T(p.Arg222Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R222Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CHST3
NM_004273.5 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 0.771

Publications

3 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_004273.5

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.953

PP5

Variant 10-72007695-C-T is Pathogenic according to our data. Variant chr10-72007695-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 6043.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
CHST3	NM_004273.5 link	c.664C>T	p.Arg222Trp	missense_variant	Exon 3 of 3	ENST00000373115.5	NP_004264.2
CHST3	NM_001441201.1 link	c.664C>T	p.Arg222Trp	missense_variant	Exon 3 of 3		NP_001428130.1
CHST3	NM_001441202.1 link	c.664C>T	p.Arg222Trp	missense_variant	Exon 3 of 3		NP_001428131.1
CHST3	XM_011540369.3 link	c.664C>T	p.Arg222Trp	missense_variant	Exon 3 of 3		XP_011538671.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHST3	ENST00000373115.5 link	c.664C>T	p.Arg222Trp	missense_variant	Exon 3 of 3	1	NM_004273.5	ENSP00000362207.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1454972

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

724038

African (AFR)

AF:

0.00

AC:

AN:

33440

American (AMR)

AF:

0.00

AC:

AN:

44582

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26072

East Asian (EAS)

AF:

0.00

AC:

AN:

39658

South Asian (SAS)

AF:

0.00

AC:

AN:

86094

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47650

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111520

Other (OTH)

AF:

0.00

AC:

AN:

60194

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Spondyloepiphyseal dysplasia with congenital joint dislocations

Pathogenic:1

Oct 01, 2010

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.85

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.22

Eigen

Benign

0.18

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.92

M_CAP

Pathogenic

0.35

MetaRNN

Pathogenic

0.95

MetaSVM

Pathogenic

0.87

MutationAssessor

Benign

0.84

PhyloP100

0.77

PrimateAI

Uncertain

0.61

PROVEAN

Benign

1.2

REVEL

Pathogenic

0.67

Sift

Benign

0.15

Sift4G

Benign

0.13

Polyphen

1.0

Vest4

0.73

MutPred

0.87

Loss of disorder (P = 0.0128);

MVP

1.0

MPC

1.7

ClinPred

0.77

GERP RS

3.6

Varity_R

0.32

gMVP

0.85

Mutation Taster

=3/97

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over