5-129904864-T-C

Variant names:

• chr5-129904864-T-C
• rs1012598884
• NM_175856.5:c.35T>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_175856.5(CHSY3):​c.35T>C​(p.Val12Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000833 in 1,320,880 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000083 (0 hom.)
• Consequence: CHSY3 NM_175856.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.14
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHSY3	NM_175856.5	c.35T>C	p.Val12Ala	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.35T>C	p.Val12Ala	missense_variant	Exon 1 of 3	1	NM_175856.5	ENSP00000302629.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000833 AC: 11 AN: 1320880 Hom.: 0 Cov.: 31 AF XY: 0.00000931 AC XY: 6 AN XY: 644778

African (AFR) AF: 0.00 AC: 0 AN: 27592

American (AMR) AF: 0.00 AC: 0 AN: 30252

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22428

East Asian (EAS) AF: 0.00 AC: 0 AN: 32184

South Asian (SAS) AF: 0.00 AC: 0 AN: 73020

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36528

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4134

European-Non Finnish (NFE) AF: 0.0000106 AC: 11 AN: 1039990

Other (OTH) AF: 0.00 AC: 0 AN: 54752

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.35T>C (p.V12A) alteration is located in exon 1 (coding exon 1) of the CHSY3 gene. This alteration results from a T to C substitution at nucleotide position 35, causing the valine (V) at amino acid position 12 to be replaced by an alanine (A). 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	0.30
BayesDel_addAF	Uncertain	0.019	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.024	T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.68	T
M_CAP	Pathogenic	0.74	D
MetaRNN	Uncertain	0.64	D
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.1	L
PhyloP100		5.1
PrimateAI	Pathogenic	0.97	D
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.25
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.014	D
Polyphen		0.99	D
Vest4		0.48
MutPred		0.30		Gain of helix (P = 0.0425);
MVP		0.76
MPC		2.0
ClinPred		0.83	D
GERP RS		2.4
PromoterAI		-0.010	Neutral
Varity_R		0.24
gMVP		0.80
Mutation Taster		=58/42	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: rs1012598884; hg19: chr5-129240557;