rs534438354

Positions:

chr2-85840338-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5

The NM_003896.4(ST3GAL5):c.1063G>A(p.Glu355Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,614,062 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

ST3GAL5
NM_003896.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:2

Conservation

PhyloP100: 7.79

Variant links:

Genes affected

ST3GAL5 (HGNC:10872): (ST3 beta-galactoside alpha-2,3-sialyltransferase 5) Ganglioside GM3 is known to participate in the induction of cell differentiation, modulation of cell proliferation, maintenance of fibroblast morphology, signal transduction, and integrin-mediated cell adhesion. The protein encoded by this gene is a type II membrane protein which catalyzes the formation of GM3 using lactosylceramide as the substrate. The encoded protein is a member of glycosyltransferase family 29 and may be localized to the Golgi apparatus. Mutation in this gene has been associated with Amish infantile epilepsy syndrome. Transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ST3GAL5 links:

ST3GAL5 (HGNC:):

ST3GAL5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-85840338-C-T is Pathogenic according to our data. Variant chr2-85840338-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 140575.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=2, Likely_pathogenic=1}. Variant chr2-85840338-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ST3GAL5	NM_003896.4 linkuse as main transcript	c.1063G>A	p.Glu355Lys	missense_variant	7/7	ENST00000638572.2	NP_003887.3	Q9UNP4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ST3GAL5	ENST00000638572.2 linkuse as main transcript	c.1063G>A	p.Glu355Lys	missense_variant	7/7	1	NM_003896.4	ENSP00000491316.1		Q9UNP4-1

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000386

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251394

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135864

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.00

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:

0.0000109

AC:

AN:

1461750

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727140

show subpopulations

Gnomad4 AFR exome

AF:

0.000478

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.000105

AC:

AN:

152312

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.000385

Gnomad4 AMR

AF:

0.00

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:

0.0000793

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

GM3 synthase deficiency

Pathogenic:3Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 27, 2020	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 15, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 01, 2022	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 355 of the ST3GAL5 protein (p.Glu355Lys). This variant is present in population databases (rs534438354, gnomAD 0.04%). This missense change has been observed in individual(s) with clinical features of ST3GAL5-related conditions (PMID: 24026681). This variant is also known as c.994G>A, p.E332K. ClinVar contains an entry for this variant (Variation ID: 140575). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects ST3GAL5 function (PMID: 30576498). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 18, 2024	Variant summary: ST3GAL5 c.1063G>A (p.Glu355Lys), also reported as E332K, results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251394 control chromosomes. c.1063G>A has been reported in the literature in the homozygous or presumed compound heterozygous states in multiple individuals affected with GM3 synthase deficiency (example, Boccuto_2014, Heide_2022). These data indicate that the variant is likely to be associated with disease. This variant was shown to lack detectable enzymatic activity in vitro and in patient cells (example, Indellicato_2019, Boccuto_2014). The following publications have been ascertained in the context of this evaluation (PMID: 24026681, 34906476, 30576498). ClinVar contains an entry for this variant (Variation ID: 140575). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 08, 2018	The ST3GAL5 c.1063G>A p.(Glu355Lys) missense variant has been reported in the literature in three siblings of African American ancestry affected with salt and pepper developmental regression syndrome (Boccuto et al. 2014). The p.Glu355Lys variant was absent in 561 normal individuals from the same geographic area (South Carolina), of which 216 were African Americans. The c.1063G>A variant is not observed in version 2.1.1 of the Genome Aggregation Database. Functional studies conducted in patient cells, animal models, in vitro and structural modelling demonstrated that this variant impacts protein function (Boccuto et al. 2014). Based on the collective evidence the c.1063G>A p.(Glu355Lys) variant is classified as pathogenic for salt and pepper developmental regression syndrome. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 16, 2023

Published functional studies demonstrate that the variant results in loss of enzyme function (Indellicato et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24026681, 35628171, 34906476, 30576498, 36833282) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.45

BayesDel_addAF

Uncertain

0.044

BayesDel_noAF

Uncertain

0.13

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.48

T;.;.;.;.;.;.;.;.;.;T;.

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.98

D;D;.;.;D;D;D;.;.;.;D;D

M_CAP

Benign

0.038

MetaRNN

Uncertain

0.74

D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Benign

-0.80

MutationAssessor

Uncertain

2.2

M;.;.;.;.;.;.;.;.;.;.;.

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-3.2

.;D;D;.;.;.;.;.;.;.;.;.

REVEL

Pathogenic

0.82

Sift

Uncertain

0.0020

.;D;D;.;.;.;.;.;.;.;.;.

Sift4G

Uncertain

0.021

.;D;D;.;.;.;.;.;.;.;.;.

Polyphen

1.0

D;D;D;D;.;.;.;D;D;D;.;D

Vest4

0.93, 0.93

MutPred

0.77

Gain of ubiquitination at E355 (P = 0.0428);.;.;.;.;.;.;.;.;.;.;.;

MVP

0.18

MPC

1.1

ClinPred

0.88

GERP RS

5.8

Varity_R

0.80

gMVP

0.81

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