1-43736342-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006279.5(ST3GAL3):c.80C>T(p.Ala27Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A27A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ST3GAL3 NM_006279.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.74

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4189244).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ST3GAL3	NM_006279.5	c.80C>T	p.Ala27Val	missense_variant	2/12	ENST00000347631.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ST3GAL3	ENST00000347631.8	c.80C>T	p.Ala27Val	missense_variant	2/12	5	NM_006279.5	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251480 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135916

Gnomad AFR exome AF: 0.00

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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461870 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727238

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.000327

EpiControl AF: 0.0000593

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

Jul 05, 2020

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with ST3GAL3-related conditions. This variant is present in population databases (rs751825349, ExAC 0.001%). This sequence change replaces alanine with valine at codon 27 of the ST3GAL3 protein (p.Ala27Val). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and valine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.056	T
BayesDel_noAF	Benign	-0.16
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.094	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.90	D
M_CAP	Benign	0.078	D
MetaRNN	Benign	0.28	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.21	D
MutationAssessor	Benign	1.8	L;L;L;L;L;L;L;.;.;.;L;.;L;L;L;L;.;L;.;.;.;L;.;.;L;L;L;L;L;L;L;L;L;L;.;.
MutationTaster	Benign	1.0	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	0.70	T
PROVEAN	Benign	-0.94	N;N;N;D;D;N;N;.;.;.;N;.;N;.;N;.;.;N;.;N;.;.;N;.;D;D;N;N;N;N;D;N;D;N;.;.
REVEL	Benign	0.11
Sift	Uncertain	0.0030	D;D;T;D;D;T;T;.;.;.;D;.;D;.;D;.;.;D;.;D;.;.;D;.;D;D;D;T;D;T;D;D;D;T;.;.
Sift4G	Uncertain	0.0090	D;D;T;D;D;D;T;.;.;.;T;.;T;.;D;.;.;D;.;D;.;.;D;.;D;D;T;D;D;D;D;T;D;D;.;.
Polyphen		0.015	B;B;B;.;P;B;B;.;.;.;.;.;B;B;D;B;.;D;.;.;.;B;.;.;P;P;B;D;.;B;P;B;.;B;.;.
Vest4		0.57
MutPred		0.40		Gain of methylation at K29 (P = 0.0829);Gain of methylation at K29 (P = 0.0829);Gain of methylation at K29 (P = 0.0829);Gain of methylation at K29 (P = 0.0829);Gain of methylation at K29 (P = 0.0829);Gain of methylation at K29 (P = 0.0829);Gain of methylation at K29 (P = 0.0829);Gain of methylation at K29 (P = 0.0829);Gain of methylation at K29 (P = 0.0829);Gain of methylation at K29 (P = 0.0829);Gain of methylation at K29 (P = 0.0829);Gain of methylation at K29 (P = 0.0829);Gain of methylation at K29 (P = 0.0829);Gain of methylation at K29 (P = 0.0829);Gain of methylation at K29 (P = 0.0829);Gain of methylation at K29 (P = 0.0829);Gain of methylation at K29 (P = 0.0829);Gain of methylation at K29 (P = 0.0829);Gain of methylation at K29 (P = 0.0829);Gain of methylation at K29 (P = 0.0829);Gain of methylation at K29 (P = 0.0829);Gain of methylation at K29 (P = 0.0829);Gain of methylation at K29 (P = 0.0829);Gain of methylation at K29 (P = 0.0829);Gain of methylation at K29 (P = 0.0829);Gain of methylation at K29 (P = 0.0829);Gain of methylation at K29 (P = 0.0829);Gain of methylation at K29 (P = 0.0829);Gain of methylation at K29 (P = 0.0829);Gain of methylation at K29 (P = 0.0829);Gain of methylation at K29 (P = 0.0829);Gain of methylation at K29 (P = 0.0829);Gain of methylation at K29 (P = 0.0829);Gain of methylation at K29 (P = 0.0829);.;.;
MVP		0.39
MPC		1.4
ClinPred		0.98	D
GERP RS		5.0
Varity_R		0.23
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs751825349; hg19: chr1-44202013;