rs534438354

chr2-85840338-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:2
• Conservation: PhyloP100: 7.79

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]

ACMG classification

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=1, Likely_pathogenic=1}. Variant chr2-85840338-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ST3GAL5	NM_003896.4	c.1063G>A	p.Glu355Lys	missense_variant	7/7	ENST00000638572.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ST3GAL5	ENST00000638572.2	c.1063G>A	p.Glu355Lys	missense_variant	7/7	1	NM_003896.4	A1

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152194 Hom.: 0 Cov.: 32

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: 5 AN: 251394 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135864

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: 16 AN: 1461750 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 727140

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: 16 AN: 152312 Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8 AN XY: 74472

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: 4

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

GM3 synthase deficiency Pathogenic:2 Uncertain:2

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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 15, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	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. -
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]. -

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	T
BayesDel_noAF	Uncertain	0.13
Cadd	Pathogenic	31
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.48	T;.;.;.;.;.;.;.;.;.;T;.
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D;D;.;.;D;D;D;.;.;.;D;D
M_CAP	Benign	0.038	D
MetaRNN	Uncertain	0.74	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.2	M;.;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.67	T
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	D
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

Other links and lift over

dbSNP: rs534438354; hg19: chr2-86067461;