1-43736383-A-G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_006279.5(ST3GAL3):​c.118+3A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

ST3GAL3
NM_006279.5 splice_region, intron

Scores

1
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.82

Publications

0 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 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ST3GAL3NM_006279.5 linkc.118+3A>G splice_region_variant, intron_variant Intron 2 of 11 ENST00000347631.8 NP_006270.1 Q11203-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ST3GAL3ENST00000347631.8 linkc.118+3A>G splice_region_variant, intron_variant Intron 2 of 11 5 NM_006279.5 ENSP00000317192.6 Q11203-1
ENSG00000284989ENST00000645057.1 linkn.*1440+3A>G splice_region_variant, intron_variant Intron 16 of 25 ENSP00000494063.1 A0A2R8Y4U1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461882
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
727242
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:
26134
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39698
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:
0.00000180
AC:
2
AN:
1112004
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
1
1
2
2
3
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

ClinVar

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

Submissions by phenotype

Developmental and epileptic encephalopathy Uncertain:1
Feb 11, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. This variant has not been reported in the literature in individuals affected with ST3GAL3-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 2 of the ST3GAL3 gene. It does not directly change the encoded amino acid sequence of the ST3GAL3 protein. It affects a nucleotide within the consensus splice site. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.070
T
BayesDel_noAF
Benign
-0.34
CADD
Uncertain
25
DANN
Benign
0.80
Eigen
Benign
-0.034
Eigen_PC
Benign
0.14
FATHMM_MKL
Uncertain
0.79
D
LIST_S2
Benign
0.72
T;T;T;T;T;T;.;.;T
M_CAP
Benign
0.044
D
MetaRNN
Benign
0.12
T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.84
T
PhyloP100
2.8
PrimateAI
Benign
0.47
T
PROVEAN
Benign
0.11
N;.;.;.;N;N;N;N;.
REVEL
Benign
0.15
Sift
Benign
0.22
T;.;.;.;T;T;T;T;.
Sift4G
Benign
0.53
T;T;.;.;T;T;T;T;.
Polyphen
0.0070, 0.025, 0.27
.;B;.;.;B;B;.;B;.
Vest4
0.37
MutPred
0.26
Loss of ubiquitination at K41 (P = 0.0041);Loss of ubiquitination at K41 (P = 0.0041);Loss of ubiquitination at K41 (P = 0.0041);Loss of ubiquitination at K41 (P = 0.0041);Loss of ubiquitination at K41 (P = 0.0041);Loss of ubiquitination at K41 (P = 0.0041);Loss of ubiquitination at K41 (P = 0.0041);Loss of ubiquitination at K41 (P = 0.0041);.;
MVP
0.082
MPC
0.80
ClinPred
0.67
D
GERP RS
4.8
PromoterAI
-0.016
Neutral
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
gMVP
0.53
Mutation Taster
=77/23
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.52
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.52
Position offset: 42
DS_DL_spliceai
0.32
Position offset: -3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

hg19: chr1-44202054; API