5-129905266-G-C

Variant names:

• chr5-129905266-G-C
• rs925007820
• NM_175856.5:c.437G>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_175856.5(CHSY3):​c.437G>C​(p.Arg146Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000213 in 1,455,306 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: CHSY3 NM_175856.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.415
• Publications: 0 publications found

Genes affected

CHSY3 (HGNC:24293): (chondroitin sulfate synthase 3) CSS3 is a glycosyltransferase that has both glucuronyltransferase and N-acetylgalactosaminyltransferase activities (Yada et al., 2003 [PubMed 12907687]).[supplied by OMIM, Mar 2008]

ENSG00000251680 (HGNC:58253):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.055702984).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHSY3	NM_175856.5	c.437G>C	p.Arg146Thr	missense_variant	Exon 1 of 3	ENST00000305031.5	NP_787052.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHSY3	ENST00000305031.5	c.437G>C	p.Arg146Thr	missense_variant	Exon 1 of 3	1	NM_175856.5	ENSP00000302629.4

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152008 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000151 AC: 1 AN: 66222 AF XY: 0.0000280

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000708

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000146 AC: 19 AN: 1303298 Hom.: 0 Cov.: 31 AF XY: 0.0000125 AC XY: 8 AN XY: 637596

African (AFR) AF: 0.00 AC: 0 AN: 27920

American (AMR) AF: 0.000275 AC: 7 AN: 25412

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19862

East Asian (EAS) AF: 0.00 AC: 0 AN: 33986

South Asian (SAS) AF: 0.0000149 AC: 1 AN: 66984

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31052

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4430

European-Non Finnish (NFE) AF: 0.00000866 AC: 9 AN: 1039328

Other (OTH) AF: 0.0000368 AC: 2 AN: 54324

GnomAD4 genome AF: 0.0000789 AC: 12 AN: 152008 Hom.: 0 Cov.: 33 AF XY: 0.000108 AC XY: 8 AN XY: 74228

African (AFR) AF: 0.00 AC: 0 AN: 41412

American (AMR) AF: 0.000720 AC: 11 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5136

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67966

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000272

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 19, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.437G>C (p.R146T) alteration is located in exon 1 (coding exon 1) of the CHSY3 gene. This alteration results from a G to C substitution at nucleotide position 437, causing the arginine (R) at amino acid position 146 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	17
DANN	Benign	0.76
DEOGEN2	Benign	0.011	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.056	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.41
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.24	N
REVEL	Benign	0.012
Sift	Benign	0.093	T
Sift4G	Benign	0.13	T
Polyphen		0.0080	B
Vest4		0.11
MutPred		0.21		Gain of phosphorylation at R146 (P = 0.0273);
MVP		0.27
MPC		1.6
ClinPred		0.048	T
GERP RS		-0.66
Varity_R		0.050
gMVP		0.47
Mutation Taster		=92/8	polymorphism

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: rs925007820; hg19: chr5-129240959;