2-241803396-C-G

Variant names:

• chr2-241803396-C-G
• rs756622639
• NM_022134.3:c.427C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_022134.3(GAL3ST2):​c.427C>G​(p.Pro143Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,314 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GAL3ST2 NM_022134.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.96

Genes affected

GAL3ST2 (HGNC:24869): (galactose-3-O-sulfotransferase 2) This gene encodes a member of the galactose-3-O-sulfotransferase protein family. The product of this gene catalyzes sulfonation by transferring a sulfate group to the hydroxyl at C-3 of nonreducing beta-galactosyl residues, and it can act on both type 1 and type 2 (Galbeta 1-3/1-4GlcNAc-R) oligosaccharides with similar efficiencies, and on core 1 glycans. This enzyme has been implicated in tumor metastasis processes. This gene is different from the GAL3ST3 gene located on chromosome 11, which has also been referred to as GAL3ST2 and encodes a related enzyme with distinct tissue distribution and substrate specificities, compared to galactose-3-O-sulfotransferase 2. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAL3ST2	NM_022134.3	c.427C>G	p.Pro143Ala	missense_variant	Exon 4 of 4	ENST00000192314.7	NP_071417.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAL3ST2	ENST00000192314.7	c.427C>G	p.Pro143Ala	missense_variant	Exon 4 of 4	1	NM_022134.3	ENSP00000192314.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248666 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134756

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS 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: 6.85e-7 AC: 1 AN: 1460314 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726320

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 18, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.427C>G (p.P143A) alteration is located in exon 4 (coding exon 4) of the GAL3ST2 gene. This alteration results from a C to G substitution at nucleotide position 427, causing the proline (P) at amino acid position 143 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	Pathogenic	0.71
BayesDel_addAF	Uncertain	0.013	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.0042	T
MetaRNN	Pathogenic	0.98	D
MetaSVM	Benign	-0.68	T
MutationAssessor	Pathogenic	2.9	M
PrimateAI	Benign	0.39	T
PROVEAN	Pathogenic	-8.0	D
REVEL	Uncertain	0.41
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.058	T
Polyphen		0.75	P
Vest4		0.76
MutPred		0.94		Loss of stability (P = 0.0465);
MVP		0.39
MPC		0.60
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.76
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs756622639; hg19: chr2-242742811;