10-72007888-T-C

Position:

• chr10-72007888-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2 PM5 PP3_Strong PP5

The ENST00000373115.5(CHST3):​c.857T>C​(p.Leu286Pro) variant causes a missense change involving the alteration of a conserved nucleotide. 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L286Q) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CHST3 ENST00000373115.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.01

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-72007888-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3061778.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 10-72007888-T-C is Pathogenic according to our data. Variant chr10-72007888-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 6047.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHST3	NM_004273.5	c.857T>C	p.Leu286Pro	missense_variant	3/3	ENST00000373115.5	NP_004264.2
CHST3	XM_006718075.5	c.857T>C	p.Leu286Pro	missense_variant	3/3		XP_006718138.1
CHST3	XM_011540369.3	c.857T>C	p.Leu286Pro	missense_variant	3/3		XP_011538671.1
CHST3	XM_047426022.1	c.857T>C	p.Leu286Pro	missense_variant	3/3		XP_047281978.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHST3	ENST00000373115.5	c.857T>C	p.Leu286Pro	missense_variant	3/3	1	NM_004273.5	ENSP00000362207	P1

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 15, 2008

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Pathogenic	3.3	M
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-7.0	D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.97		Gain of disorder (P = 0.011);
MVP		0.96
MPC		2.1
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.99
gMVP		0.98

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: rs121908620; hg19: chr10-73767646;