chr10-72008019-C-T

Variant names:

• chr10-72008019-C-T
• rs267606732
• NM_004273.5:c.988C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_004273.5(CHST3):​c.988C>T​(p.Gln330*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000716 in 1,397,202 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 Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: CHST3 NM_004273.5 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.82
• Publications: 1 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 7 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 14 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-72008019-C-T is Pathogenic according to our data. Variant chr10-72008019-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 6051.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHST3	NM_004273.5	MANE Select	c.988C>T	p.Gln330*	stop_gained	Exon 3 of 3	NP_004264.2
	CHST3	NM_001441201.1		c.988C>T	p.Gln330*	stop_gained	Exon 3 of 3	NP_001428130.1
	CHST3	NM_001441202.1		c.988C>T	p.Gln330*	stop_gained	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.988C>T	p.Gln330*	stop_gained	Exon 3 of 3	ENSP00000362207.4
	CHST3	ENST00000879006.1		c.988C>T	p.Gln330*	stop_gained	Exon 3 of 3	ENSP00000549065.1
	CHST3	ENST00000943244.1		c.988C>T	p.Gln330*	stop_gained	Exon 3 of 3	ENSP00000613303.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.16e-7 AC: 1 AN: 1397202 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 689162

African (AFR) AF: 0.00 AC: 0 AN: 31560

American (AMR) AF: 0.00 AC: 0 AN: 35676

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 35716

South Asian (SAS) AF: 0.00 AC: 0 AN: 79216

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47966

Middle Eastern (MID) AF: 0.000182 AC: 1 AN: 5504

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078492

Other (OTH) AF: 0.00 AC: 0 AN: 57932

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Uncertain	0.39
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.84	D
PhyloP100		2.8
Vest4		0.57
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Mutation Taster		=4/196	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: rs267606732; hg19: chr10-73767777;