rs777739643

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004273.5(CHST3):c.1031A>G(p.Asn344Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000646 in 1,548,816 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000064 ( 0 hom. )

Consequence

CHST3
NM_004273.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.22

Publications

0 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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
CHST3	NM_004273.5 link	c.1031A>G	p.Asn344Ser	missense_variant	Exon 3 of 3	ENST00000373115.5	NP_004264.2
CHST3	NM_001441201.1 link	c.1031A>G	p.Asn344Ser	missense_variant	Exon 3 of 3		NP_001428130.1
CHST3	NM_001441202.1 link	c.1031A>G	p.Asn344Ser	missense_variant	Exon 3 of 3		NP_001428131.1
CHST3	XM_011540369.3 link	c.1031A>G	p.Asn344Ser	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.1031A>G	p.Asn344Ser	missense_variant	Exon 3 of 3	1	NM_004273.5	ENSP00000362207.4

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000135

AC:

AN:

148210

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000408

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:

0.00000644

AC:

AN:

1396656

Hom.:

Cov.:

AF XY:

0.00000726

AC XY:

AN XY:

688812

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31540

American (AMR)

AF:

0.0000280

AC:

AN:

35662

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25140

East Asian (EAS)

AF:

0.00

AC:

AN:

35706

South Asian (SAS)

AF:

0.0000379

AC:

AN:

79182

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47960

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5248

European-Non Finnish (NFE)

AF:

0.00000371

AC:

AN:

1078338

Other (OTH)

AF:

0.0000173

AC:

AN:

57880

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

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

AF:

0.00000657

AC:

AN:

152160

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74322

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41456

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00316

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68008

Other (OTH)

AF:

0.00

AC:

AN:

2090

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000217

AC:

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

Feb 21, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with CHST3-related disease. While this variant is present in population databases (rs777739643), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This sequence change replaces asparagine with serine at codon 344 of the CHST3 protein (p.Asn344Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.087

BayesDel_noAF

Benign

-0.24

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.20

Eigen

Pathogenic

0.73

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.86

M_CAP

Benign

0.047

MetaRNN

Uncertain

0.67

MetaSVM

Uncertain

0.30

MutationAssessor

Uncertain

2.5

PhyloP100

7.2

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-0.65

REVEL

Uncertain

0.51

Sift

Benign

0.17

Sift4G

Benign

0.10

Polyphen

1.0

Vest4

0.58

MutPred

0.68

Loss of catalytic residue at N344 (P = 0.0057);

MVP

0.92

MPC

1.1

ClinPred

0.46

GERP RS

5.5

Varity_R

0.27

gMVP

0.89

Mutation Taster

=58/42

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over