Genetic Variant GAL3ST3:p.Glu388Lys (chr11-66042641-C-T) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_033036.3(GAL3ST3):c.1162G>A(p.Glu388Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000195 in 1,535,684 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

GAL3ST3
NM_033036.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.58

Variant links:

Genes affected

GAL3ST3 (HGNC:24144): (galactose-3-O-sulfotransferase 3) 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 3' position of galactose in N-acetyllactosamine in both type 2 (Gal-beta-1-4GlcNAc-R) oligosaccharides and core-2-branched O-glycans, but not on type 1 or core-1-branched structures. This gene, which has also been referred to as GAL3ST2, is different from the GAL3ST2 gene located on chromosome 2 that encodes a related enzyme with distinct tissue distribution and substrate specificities, compared to galactose-3-O-sulfotransferase 3. [provided by RefSeq, Jul 2008]

GAL3ST3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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, 0.971

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAL3ST3	NM_033036.3 link	c.1162G>A	p.Glu388Lys	missense_variant	Exon 3 of 3	ENST00000312006.5	NP_149025.1	Q96A11
GAL3ST3	XM_017018519.2 link	c.1228G>A	p.Glu410Lys	missense_variant	Exon 2 of 2		XP_016874008.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAL3ST3	ENST00000312006.5 link	c.1162G>A	p.Glu388Lys	missense_variant	Exon 3 of 3	1	NM_033036.3	ENSP00000308591.3		Q96A11
GAL3ST3	ENST00000527878.1 link	c.1162G>A	p.Glu388Lys	missense_variant	Exon 2 of 2	1		ENSP00000434829.1		Q96A11

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151832

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.00

GnomAD4 exome

AF:

0.00000145

AC:

AN:

1383852

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

683020

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

9.27e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000659

AC:

AN:

151832

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74146

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 29, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1162G>A (p.E388K) alteration is located in exon 3 (coding exon 2) of the GAL3ST3 gene. This alteration results from a G to A substitution at nucleotide position 1162, causing the glutamic acid (E) at amino acid position 388 to be replaced by a lysine (K). 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

0.99

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.11

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

T;T

Eigen

Pathogenic

0.73

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.81

.;T

M_CAP

Benign

0.017

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Benign

-0.88

MutationAssessor

Uncertain

2.8

M;M

PrimateAI

Pathogenic

0.91

PROVEAN

Uncertain

-3.8

D;D

REVEL

Uncertain

0.48

Sift

Uncertain

0.012

D;D

Sift4G

Uncertain

0.035

D;D

Polyphen

1.0

D;D

Vest4

0.96

MutPred

0.93

Gain of MoRF binding (P = 0.012);Gain of MoRF binding (P = 0.012);

MVP

0.72

MPC

1.1

ClinPred

0.99

GERP RS

4.7

Varity_R

0.63

gMVP

0.99

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over