rs777739643

Variant names:

• chr10-72008062-A-G
• rs777739643
• NM_004273.5:c.1031A>G

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.22
• Publications: 0 publications found

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, G2P, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004273.5. 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
	CHST3	NM_004273.5	MANE Select	c.1031A>G	p.Asn344Ser	missense	Exon 3 of 3	NP_004264.2
	CHST3	NM_001441201.1		c.1031A>G	p.Asn344Ser	missense	Exon 3 of 3	NP_001428130.1
	CHST3	NM_001441202.1		c.1031A>G	p.Asn344Ser	missense	Exon 3 of 3	NP_001428131.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHST3	ENST00000373115.5	TSL:1 MANE Select	c.1031A>G	p.Asn344Ser	missense	Exon 3 of 3	ENSP00000362207.4	Q7LGC8
	CHST3	ENST00000879006.1		c.1031A>G	p.Asn344Ser	missense	Exon 3 of 3	ENSP00000549065.1
	CHST3	ENST00000943244.1		c.1031A>G	p.Asn344Ser	missense	Exon 3 of 3	ENSP00000613303.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152160 Hom.: 0 Cov.: 33

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: 2 AN: 148210 AF XY: 0.00

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: 9 AN: 1396656 Hom.: 0 Cov.: 31 AF XY: 0.00000726 AC XY: 5 AN XY: 688812

African (AFR) AF: 0.00 AC: 0 AN: 31540

American (AMR) AF: 0.0000280 AC: 1 AN: 35662

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25140

East Asian (EAS) AF: 0.00 AC: 0 AN: 35706

South Asian (SAS) AF: 0.0000379 AC: 3 AN: 79182

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47960

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5248

European-Non Finnish (NFE) AF: 0.00000371 AC: 4 AN: 1078338

Other (OTH) AF: 0.0000173 AC: 1 AN: 57880

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152160 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74322

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

African (AFR) AF: 0.00 AC: 0 AN: 41456

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00316 AC: 1 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68008

Other (OTH) AF: 0.00 AC: 0 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.

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000217 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Spondyloepiphyseal dysplasia with congenital joint dislocations (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.087	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.20	T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.047	D
MetaRNN	Uncertain	0.67	D
MetaSVM	Uncertain	0.30	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		7.2
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.65	N
REVEL	Uncertain	0.51
Sift	Benign	0.17	T
Sift4G	Benign	0.10	T
Polyphen		1.0	D
Vest4		0.58
MutPred		0.68		Loss of catalytic residue at N344 (P = 0.0057)
MVP		0.92
MPC		1.1
ClinPred		0.46	T
GERP RS		5.5
Varity_R		0.27
gMVP		0.89
Mutation Taster		=58/42	polymorphism

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

Other links and lift over

dbSNP: rs777739643; hg19: chr10-73767820;