rs201877149
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_170601.5(SIAE):āc.1211T>Cā(p.Phe404Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000112 in 1,614,000 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: š 0.00022 ( 0 hom., cov: 32)
Exomes š: 0.00010 ( 0 hom. )
Consequence
SIAE
NM_170601.5 missense
NM_170601.5 missense
Scores
3
7
9
Clinical Significance
Conservation
PhyloP100: 4.71
Genes affected
SIAE (HGNC:18187): (sialic acid acetylesterase) This gene encodes an enzyme which removes 9-O-acetylation modifications from sialic acids. Mutations in this gene are associated with susceptibility to autoimmune disease 6. Multiple transcript variants encoding different isoforms, found either in the cytosol or in the lysosome, have been found for this gene.[provided by RefSeq, Feb 2011]
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ACMG classification
Classification made for transcript
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 | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SIAE | NM_170601.5 | c.1211T>C | p.Phe404Ser | missense_variant | 9/10 | ENST00000263593.8 | NP_733746.1 | |
SIAE | NM_001199922.2 | c.1106T>C | p.Phe369Ser | missense_variant | 11/12 | NP_001186851.1 | ||
SIAE | XM_047427132.1 | c.638T>C | p.Phe213Ser | missense_variant | 6/7 | XP_047283088.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SIAE | ENST00000263593.8 | c.1211T>C | p.Phe404Ser | missense_variant | 9/10 | 1 | NM_170601.5 | ENSP00000263593.3 | ||
SIAE | ENST00000618733.4 | c.1106T>C | p.Phe369Ser | missense_variant | 11/12 | 1 | ENSP00000478211.1 | |||
SIAE | ENST00000545756.5 | c.1106T>C | p.Phe369Ser | missense_variant | 10/11 | 5 | ENSP00000437877.1 |
Frequencies
GnomAD3 genomes AF: 0.000217 AC: 33AN: 152120Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000171 AC: 43AN: 251456Hom.: 0 AF XY: 0.000162 AC XY: 22AN XY: 135908
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GnomAD4 exome AF: 0.000101 AC: 147AN: 1461880Hom.: 0 Cov.: 31 AF XY: 0.000103 AC XY: 75AN XY: 727244
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GnomAD4 genome AF: 0.000217 AC: 33AN: 152120Hom.: 0 Cov.: 32 AF XY: 0.000256 AC XY: 19AN XY: 74306
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 01, 2023 | Variant summary: SIAE c.1211T>C (p.Phe404Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00017 in 251456 control chromosomes. This frequency does not allow conclusions about variant significance. c.1211T>C has been reported in the literature in individuals with diseases of an autoimmune etiology such as SLE, Juvenile idiopathic arthritis, Primary Biliary Cirrhosis and in unaffected controls (example, Surolia_2010, Hirschfield_2012, Sevdali_2017). These report(s) do not provide unequivocal conclusions about a penetrant association of the variant with Autoimmune Disease, Susceptibility To, 6. At least one publication reports experimental evidence evaluating an impact on protein function (Surolia_2010). The most pronounced variant effect results in >50% of normal esterase activity with the authors characterizing it as esterase and secretion defective. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 12, 2023 | This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 404 of the SIAE protein (p.Phe404Ser). This variant is present in population databases (rs201877149, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with autoimmune disease or biliary cirrhosis (PMID: 20555325, 22257840). ClinVar contains an entry for this variant (Variation ID: 1353). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects SIAE function (PMID: 20555325). 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. - |
Autoimmune disease, susceptibility to, 6 Other:1
risk factor, no assertion criteria provided | literature only | OMIM | Jul 08, 2010 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
T;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T;.
M_CAP
Benign
D
MetaRNN
Uncertain
D;D;D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;.;.
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;.
REVEL
Uncertain
Sift
Benign
T;T;.
Sift4G
Benign
T;T;T
Polyphen
B;.;.
Vest4
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at