10-72007558-CG-CGG

Position:

• chr10-72007558-CG-CGG

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_004273.5(CHST3):​c.533dup​(p.Ala179ArgfsTer141) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,606,802 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: CHST3 NM_004273.5 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: -1.77

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 4 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-72007558-C-CG is Pathogenic according to our data. Variant chr10-72007558-C-CG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 432012.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHST3	NM_004273.5	c.533dup	p.Ala179ArgfsTer141	frameshift_variant	3/3	ENST00000373115.5	NP_004264.2
CHST3	XM_006718075.5	c.533dup	p.Ala179ArgfsTer141	frameshift_variant	3/3		XP_006718138.1
CHST3	XM_011540369.3	c.533dup	p.Ala179ArgfsTer141	frameshift_variant	3/3		XP_011538671.1
CHST3	XM_047426022.1	c.533dup	p.Ala179ArgfsTer141	frameshift_variant	3/3		XP_047281978.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHST3	ENST00000373115.5	c.533dup	p.Ala179ArgfsTer141	frameshift_variant	3/3	1	NM_004273.5	ENSP00000362207	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152208 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: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000297 AC: 7 AN: 235956 Hom.: 0 AF XY: 0.0000309 AC XY: 4 AN XY: 129526

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000112

Gnomad SAS exome AF: 0.000132

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000941

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000151 AC: 22 AN: 1454594 Hom.: 0 Cov.: 31 AF XY: 0.0000207 AC XY: 15 AN XY: 723882

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: 0.000221

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152208 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74368

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spondyloepiphyseal dysplasia with congenital joint dislocations Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 23, 2022	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the CHST3 protein in which other variant(s) (p.Leu286Trpfs*48) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 432012). This premature translational stop signal has been observed in individuals with CHST3-related conditions (PMID: 20830804, 27753269; Invitae). This variant is present in population databases (rs774572727, gnomAD 0.01%). This sequence change creates a premature translational stop signal (p.Ala179Argfs*141) in the CHST3 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 301 amino acid(s) of the CHST3 protein. -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	-	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). The variant is predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by more than 10%. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000432012). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences	-	This mutation leads to frameshift mutation (p.A179R fs*141) and was found to be pathogenic by in silico tools. Parents were found to be heterozygous carriers. -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 12, 2017	The c.533dupG variant in the CHST3 gene has been reported previously in the homozygous state, using alternate nomenclature of c.533_534insG, in two unrelated Arab individuals affected with carbohydrate sulfotransferase 3 deficiency, congenital joint dislocations, and short stature (Unger et al., 2010). The same homozygous variant was also reported in a child of Indian descent with extreme short stature, joint contractures and prominence, and vertebral abnormalities (Srivastava et al., 2017). The c.533dupG variant causes a frameshift starting with codon Alanine 179, changes this amino acid to am Arginine residue, and creates a premature Stop codon at position 141 of the new reading frame, denoted p.Ala179ArgfsX141. This variant is predicted to cause loss of normal protein function through protein truncation. The c.533dupG variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret c.533dupG as a likely pathogenic variant. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2018	- -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs769540174; hg19: chr10-73767316;