rs201877149

Variant names:

Variant summary

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

The NM_170601.5(SIAE):c.1211T>C(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 (★★).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

SIAE
NM_170601.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2O:1

Conservation

PhyloP100: 4.71

Publications

9 publications found

Variant links:

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]

SIAE Gene-Disease associations (from GenCC):

autoimmune disease, susceptibility to, 6
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine

SIAE links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIAE	NM_170601.5 link	c.1211T>C	p.Phe404Ser	missense_variant	Exon 9 of 10	ENST00000263593.8	NP_733746.1	Q9HAT2-1
SIAE	NM_001199922.2 link	c.1106T>C	p.Phe369Ser	missense_variant	Exon 11 of 12		NP_001186851.1	Q9HAT2-2
SIAE	XM_047427132.1 link	c.638T>C	p.Phe213Ser	missense_variant	Exon 6 of 7		XP_047283088.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SIAE	ENST00000263593.8 link	c.1211T>C	p.Phe404Ser	missense_variant	Exon 9 of 10	1	NM_170601.5	ENSP00000263593.3	Q9HAT2-1
SIAE	ENST00000618733.4 link	c.1106T>C	p.Phe369Ser	missense_variant	Exon 11 of 12	1		ENSP00000478211.1	Q9HAT2-2
SIAE	ENST00000545756.5 link	c.1106T>C	p.Phe369Ser	missense_variant	Exon 10 of 11	5		ENSP00000437877.1	Q9HAT2-2

Frequencies

GnomAD3 genomes

AF:

0.000217

AC:

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000590

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000171

AC:

AN:

251456

AF XY:

0.000162

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000318

Gnomad ASJ exome

AF:

0.00179

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000105

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000101

AC:

147

AN:

1461880

Hom.:

Cov.:

AF XY:

0.000103

AC XY:

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.000179

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00180

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000665

AC:

AN:

1112000

Other (OTH)

AF:

0.000265

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

AF:

0.000217

AC:

AN:

152120

Hom.:

Cov.:

AF XY:

0.000256

AC XY:

AN XY:

74306

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41414

American (AMR)

AF:

0.000590

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00346

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000162

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.533

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000234

Hom.:

Bravo

AF:

0.000219

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000107

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000178

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

Feb 01, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Jul 08, 2010

OMIM

Significance:risk factor

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Pathogenic

0.32

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.50

T;.;.

Eigen

Benign

0.070

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.77

T;T;.

M_CAP

Benign

0.041

MetaRNN

Uncertain

0.69

D;D;D

MetaSVM

Benign

-0.45

MutationAssessor

Uncertain

2.7

M;.;.

PhyloP100

4.7

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-5.8

D;D;.

REVEL

Uncertain

0.63

Sift

Benign

0.054

T;T;.

Sift4G

Benign

0.10

T;T;T

Polyphen

0.44

B;.;.

Vest4

0.95

MVP

0.63

MPC

0.57

ClinPred

0.84

GERP RS

4.3

Varity_R

0.47

gMVP

0.86

Mutation Taster

=20/80

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over