rs948699026

chr1-43894423-C-Gchr1-43894423-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006279.5(ST3GAL3):c.343C>G(p.Arg115Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,614,048 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R115C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: ST3GAL3 NM_006279.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.53

Genes affected

ST3GAL3 (HGNC:10866): (ST3 beta-galactoside alpha-2,3-sialyltransferase 3) The protein encoded by this gene is a type II membrane protein that catalyzes the transfer of sialic acid from CMP-sialic acid to galactose-containing substrates. The encoded protein is normally found in the Golgi apparatus but can be proteolytically processed to a soluble form. This protein is a member of glycosyltransferase family 29. Mutations in this gene have been associated with a form of autosomal recessive nonsymdromic cognitive disability as well as infantile epileptic encephalopathy. Multiple transcript variants encoding several different isoforms have been found for this gene. [provided by RefSeq, Jul 2017]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ST3GAL3	NM_006279.5	c.343C>G	p.Arg115Gly	missense_variant	6/12	ENST00000347631.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ST3GAL3	ENST00000347631.8	c.343C>G	p.Arg115Gly	missense_variant	6/12	5	NM_006279.5	A1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461892 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727246

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: 0.00000629

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152156 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74348

Gnomad4 AFR AF: 0.00

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: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 04, 2020

This variant has not been reported in the literature in individuals with a ST3GAL3-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with glycine at codon 115 of the ST3GAL3 protein (p.Arg115Gly). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and glycine. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, this variant has uncertain impact on ST3GAL3 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Benign	0.15	T;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.85	D
M_CAP	Uncertain	0.25	D
MetaRNN	Uncertain	0.54	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.0052	D
MutationAssessor	Benign	1.2	L;.;.;.;.;.;.;.;.;.;L;.;.;L;.;.;.;.;L;.;.;L;.;L;.;L;.;.;.;.;.;.
MutationTaster	Benign	0.94	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.68	T
REVEL	Benign	0.19
Polyphen		0.82	P;P;P;.;D;P;.;.;.;.;P;D;P;P;.;P;.;.;P;.;.;D;D;P;D;.;P;D;.;D;.;.
Vest4		0.56, 0.60, 0.70, 0.58, 0.58, 0.57, 0.66, 0.72, 0.58, 0.55, 0.57, 0.59, 0.58
MutPred		0.57		Loss of MoRF binding (P = 0.0131);.;.;.;.;.;Loss of MoRF binding (P = 0.0131);.;.;.;Loss of MoRF binding (P = 0.0131);.;.;Loss of MoRF binding (P = 0.0131);Loss of MoRF binding (P = 0.0131);.;Loss of MoRF binding (P = 0.0131);Loss of MoRF binding (P = 0.0131);Loss of MoRF binding (P = 0.0131);.;.;Loss of MoRF binding (P = 0.0131);.;Loss of MoRF binding (P = 0.0131);.;Loss of MoRF binding (P = 0.0131);.;.;.;.;.;.;
MVP		0.67
MPC		0.78
ClinPred		0.87	D
GERP RS		4.0
Varity_R		0.17
gMVP		0.71

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: rs948699026; hg19: chr1-44360095;