rs121908616

Variant names:

• chr10-72007807-T-C
• rs121908616
• NM_004273.5:c.776T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_004273.5(CHST3):​c.776T>C​(p.Leu259Pro) variant causes a missense change. 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 Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. L259L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CHST3 NM_004273.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.16
• Publications: 5 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, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_004273.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983
• PP5: Variant 10-72007807-T-C is Pathogenic according to our data. Variant chr10-72007807-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 6041.Status of the report is no_assertion_criteria_provided, 0 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHST3	NM_004273.5	MANE Select	c.776T>C	p.Leu259Pro	missense	Exon 3 of 3	NP_004264.2
	CHST3	NM_001441201.1		c.776T>C	p.Leu259Pro	missense	Exon 3 of 3	NP_001428130.1
	CHST3	NM_001441202.1		c.776T>C	p.Leu259Pro	missense	Exon 3 of 3	NP_001428131.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHST3	ENST00000373115.5	TSL:1 MANE Select	c.776T>C	p.Leu259Pro	missense	Exon 3 of 3	ENSP00000362207.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Spondyloepiphyseal dysplasia with congenital joint dislocations Pathogenic:1

Oct 01, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.60	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		6.2
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-4.2	D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.92		Gain of disorder (P = 0.0109)
MVP		0.99
MPC		2.1
ClinPred		0.98	D
GERP RS		5.8
Varity_R		0.96
gMVP		0.97
Mutation Taster		=9/91	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: rs121908616; hg19: chr10-73767565;