1-43736285-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_006279.5(ST3GAL3):​c.23G>T​(p.Arg8Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,868 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R8H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ST3GAL3
NM_006279.5 missense

Scores

9
5
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.71

Publications

1 publications found
Variant links:
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]
ST3GAL3 Gene-Disease associations (from GenCC):
  • developmental and epileptic encephalopathy, 15
    Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
  • intellectual disability, autosomal recessive 12
    Inheritance: AR Classification: STRONG Submitted by: G2P
  • complex neurodevelopmental disorder
    Inheritance: AR Classification: MODERATE Submitted by: ClinGen
  • infantile spasms
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • autosomal recessive non-syndromic intellectual disability
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.84

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ST3GAL3NM_006279.5 linkc.23G>T p.Arg8Leu missense_variant Exon 2 of 12 ENST00000347631.8 NP_006270.1 Q11203-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ST3GAL3ENST00000347631.8 linkc.23G>T p.Arg8Leu missense_variant Exon 2 of 12 5 NM_006279.5 ENSP00000317192.6 Q11203-1
ENSG00000284989ENST00000645057.1 linkn.*1345G>T non_coding_transcript_exon_variant Exon 16 of 26 ENSP00000494063.1 A0A2R8Y4U1
ENSG00000284989ENST00000645057.1 linkn.*1345G>T 3_prime_UTR_variant Exon 16 of 26 ENSP00000494063.1 A0A2R8Y4U1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD2 exomes
AF:
0.00000398
AC:
1
AN:
251486
AF XY:
0.00000736
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS 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:
6.84e-7
AC:
1
AN:
1461868
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
727232
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.0000224
AC:
1
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26132
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39696
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86258
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53420
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1111994
Other (OTH)
AF:
0.00
AC:
0
AN:
60396
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000756

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy Uncertain:1
May 25, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 8 of the ST3GAL3 protein (p.Arg8Leu). This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with ST3GAL3-related conditions. 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: "Not Available"; Align-GVGD: "Class C0"). 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.73
BayesDel_addAF
Pathogenic
0.32
D
BayesDel_noAF
Pathogenic
0.31
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Benign
0.17
T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.
Eigen
Pathogenic
0.76
Eigen_PC
Pathogenic
0.79
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Pathogenic
0.98
.;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;.;.
M_CAP
Benign
0.041
D
MetaRNN
Pathogenic
0.84
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;D;D
MetaSVM
Uncertain
0.22
D
MutationAssessor
Benign
1.9
L;L;L;L;L;L;L;.;.;.;L;.;L;L;L;L;.;L;.;.;.;L;.;.;L;L;L;L;L;L;L;L;L;L
PhyloP100
6.7
PrimateAI
Pathogenic
0.91
D
PROVEAN
Benign
-2.2
N;N;N;D;D;D;N;.;.;.;N;.;D;.;N;.;.;N;.;N;.;.;N;.;D;D;N;D;D;D;D;N;D;D
REVEL
Uncertain
0.57
Sift
Uncertain
0.0040
D;D;D;D;D;D;D;.;.;.;D;.;D;.;D;.;.;D;.;D;.;.;D;.;D;D;D;D;D;D;D;D;D;D
Sift4G
Uncertain
0.017
D;D;T;D;D;D;D;.;.;.;D;.;D;.;D;.;.;D;.;D;.;.;D;.;D;D;D;D;D;D;D;T;D;D
Polyphen
0.99
D;D;D;.;D;D;D;.;.;.;.;.;D;D;D;D;.;D;.;.;.;D;.;.;D;D;D;D;.;D;D;D;.;D
Vest4
0.83
MutPred
0.73
Loss of sheet (P = 0.0483);Loss of sheet (P = 0.0483);Loss of sheet (P = 0.0483);Loss of sheet (P = 0.0483);Loss of sheet (P = 0.0483);Loss of sheet (P = 0.0483);Loss of sheet (P = 0.0483);Loss of sheet (P = 0.0483);Loss of sheet (P = 0.0483);Loss of sheet (P = 0.0483);Loss of sheet (P = 0.0483);Loss of sheet (P = 0.0483);Loss of sheet (P = 0.0483);Loss of sheet (P = 0.0483);Loss of sheet (P = 0.0483);Loss of sheet (P = 0.0483);Loss of sheet (P = 0.0483);Loss of sheet (P = 0.0483);Loss of sheet (P = 0.0483);Loss of sheet (P = 0.0483);Loss of sheet (P = 0.0483);Loss of sheet (P = 0.0483);Loss of sheet (P = 0.0483);Loss of sheet (P = 0.0483);Loss of sheet (P = 0.0483);Loss of sheet (P = 0.0483);Loss of sheet (P = 0.0483);Loss of sheet (P = 0.0483);Loss of sheet (P = 0.0483);Loss of sheet (P = 0.0483);Loss of sheet (P = 0.0483);Loss of sheet (P = 0.0483);Loss of sheet (P = 0.0483);Loss of sheet (P = 0.0483);
MVP
0.95
MPC
0.71
ClinPred
0.94
D
GERP RS
5.9
PromoterAI
-0.024
Neutral
Varity_R
0.16
gMVP
0.75
Mutation Taster
=54/46
polymorphism

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

Other links and lift over

dbSNP: rs900948973; hg19: chr1-44201956; API