dbSNP rs1057520111: CHST3:p.Ser351Tyr (chr10-72008083-C-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_004273.5(CHST3):c.1052C>A(p.Ser351Tyr) variant causes a missense change involving the alteration of a 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 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

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.89

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.863

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHST3	NM_004273.5 link	c.1052C>A	p.Ser351Tyr	missense_variant	Exon 3 of 3	ENST00000373115.5	NP_004264.2	Q7LGC8
CHST3	XM_006718075.5 link	c.1052C>A	p.Ser351Tyr	missense_variant	Exon 3 of 3		XP_006718138.1	Q7LGC8
CHST3	XM_011540369.3 link	c.1052C>A	p.Ser351Tyr	missense_variant	Exon 3 of 3		XP_011538671.1	Q7LGC8
CHST3	XM_047426022.1 link	c.1052C>A	p.Ser351Tyr	missense_variant	Exon 3 of 3		XP_047281978.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHST3	ENST00000373115.5 link	c.1052C>A	p.Ser351Tyr	missense_variant	Exon 3 of 3	1	NM_004273.5	ENSP00000362207.4		Q7LGC8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1393272

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

686952

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Spondyloepiphyseal dysplasia with congenital joint dislocations

Uncertain:1

Nov 15, 2018

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

The homozygous p.Ser351Tyr variant in CHST3 was identified by our study in one individual with Spondyloepiphyseal Dysplasia with Congenital Joint Dislocations. This variant was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. An additional variant at the same position, p.Ser351Phe), has been reported in ClinVar as without any disease association, slightly supporting that a change at this position may not be tolerated (ClinVar ID: 377035). In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Ser351Tyr variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.32

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.37

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

M_CAP

Uncertain

0.18

MetaRNN

Pathogenic

0.86

MetaSVM

Uncertain

0.44

MutationAssessor

Uncertain

2.4

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-2.2

REVEL

Pathogenic

0.78

Sift

Uncertain

0.0010

Sift4G

Benign

0.074

Polyphen

1.0

Vest4

0.90

MutPred

0.53

Loss of disorder (P = 0.028);

MVP

0.93

MPC

1.9

ClinPred

0.98

GERP RS

5.5

Varity_R

0.83

gMVP

0.94

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over