10-72008083-C-T

Variant names:

• chr10-72008083-C-T
• rs1057520111
• NM_004273.5:c.1052C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_004273.5(CHST3):​c.1052C>T​(p.Ser351Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000718 in 1,393,272 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S351Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: CHST3 NM_004273.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.89
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.88
• PP5: Variant 10-72008083-C-T is Pathogenic according to our data. Variant chr10-72008083-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 377035.Status of the report is criteria_provided_single_submitter, 1 stars.

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.1052C>T	p.Ser351Phe	missense	Exon 3 of 3	NP_004264.2
	CHST3	NM_001441201.1		c.1052C>T	p.Ser351Phe	missense	Exon 3 of 3	NP_001428130.1
	CHST3	NM_001441202.1		c.1052C>T	p.Ser351Phe	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.1052C>T	p.Ser351Phe	missense	Exon 3 of 3	ENSP00000362207.4	Q7LGC8
	CHST3	ENST00000879006.1		c.1052C>T	p.Ser351Phe	missense	Exon 3 of 3	ENSP00000549065.1
	CHST3	ENST00000943244.1		c.1052C>T	p.Ser351Phe	missense	Exon 3 of 3	ENSP00000613303.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.18e-7 AC: 1 AN: 1393272 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 686952

African (AFR) AF: 0.00 AC: 0 AN: 31470

American (AMR) AF: 0.00 AC: 0 AN: 35534

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25078

East Asian (EAS) AF: 0.00 AC: 0 AN: 35656

South Asian (SAS) AF: 0.0000127 AC: 1 AN: 78922

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47922

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4928

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1076020

Other (OTH) AF: 0.00 AC: 0 AN: 57742

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	0.44	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		7.9
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-2.7	D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.59		Loss of disorder (P = 0.0167)
MVP		0.94
MPC		1.7
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.90
gMVP		0.94
Mutation Taster		=11/89	disease causing (ClinVar)

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: rs1057520111; hg19: chr10-73767841;