rs143070599

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_170601.5(SIAE):c.587G>T(p.Cys196Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000753 in 1,614,208 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00060 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00077 ( 1 hom. )

Consequence

SIAE
NM_170601.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4O:1

Conservation

PhyloP100: 6.86

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.902

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIAE	NM_170601.5 link	c.587G>T	p.Cys196Phe	missense_variant	Exon 5 of 10	ENST00000263593.8	NP_733746.1	Q9HAT2-1
SIAE	NM_001199922.2 link	c.482G>T	p.Cys161Phe	missense_variant	Exon 7 of 12		NP_001186851.1	Q9HAT2-2
SIAE	XM_047427132.1 link	c.14G>T	p.Cys5Phe	missense_variant	Exon 2 of 7		XP_047283088.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SIAE	ENST00000263593.8 link	c.587G>T	p.Cys196Phe	missense_variant	Exon 5 of 10	1	NM_170601.5	ENSP00000263593.3	Q9HAT2-1
SIAE	ENST00000618733.4 link	c.482G>T	p.Cys161Phe	missense_variant	Exon 7 of 12	1		ENSP00000478211.1	Q9HAT2-2
SIAE	ENST00000545756.5 link	c.482G>T	p.Cys161Phe	missense_variant	Exon 6 of 11	5		ENSP00000437877.1	Q9HAT2-2

Frequencies

GnomAD3 genomes

AF:

0.000598

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00103

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000378

AC:

AN:

251464

Hom.:

AF XY:

0.000419

AC XY:

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000231

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:

0.000712

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.000769

AC:

1124

AN:

1461872

Hom.:

Cov.:

AF XY:

0.000759

AC XY:

552

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.000402

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000951

Gnomad4 OTH exome

AF:

0.000712

GnomAD4 genome

AF:

0.000597

AC:

AN:

152336

Hom.:

Cov.:

AF XY:

0.000497

AC XY:

AN XY:

74504

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.00105

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00103

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000807

Hom.:

Bravo

AF:

0.000767

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.000428

AC:

EpiCase

AF:

0.000600

EpiControl

AF:

0.00113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Apr 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SIAE: PM2, PS4:Moderate, PS3:Supporting -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 196 of the SIAE protein (p.Cys196Phe). This variant is present in population databases (rs143070599, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with autoimmune disease (PMID: 20555325). ClinVar contains an entry for this variant (Variation ID: 1351). 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, 23308225). 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. -

not specified

Uncertain:1

Jan 17, 2025

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.587G>T (p.Cys196Phe) results in a non-conservative amino acid change located in the Sialate O-acetylesterase domain (IPR005181) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00038 in 251464 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in SIAE causing Autoimmune Disease, Susceptibility To, 6, allowing no conclusion about variant significance. c.587G>T has been reported in the literature in individuals affected with Autoimmune Disease, Susceptibility To, 6. These report(s) do not provide unequivocal conclusions about association of the variant with Autoimmune Disease, Susceptibility To, 6 (Surolia_2010). However, subsequent studies have reported this variant in similar numbers of disease cases and controls, with an odd ratio of 1.0145 (Hunt_2012, Gan_2012). Two publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity in both studies (Surolia_2010, Chellappa_2013). The following publications have been ascertained in the context of this evaluation (PMID: 23308225, 23011869, 22200769, 20555325). ClinVar contains an entry for this variant (Variation ID: 1351). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

SIAE-related disorder

Uncertain:1

Nov 11, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SIAE c.587G>T variant is predicted to result in the amino acid substitution p.Cys196Phe. This variant has been reported in individuals with autoimmune diseases (Surolia et al. 2010. PubMed ID: 20555325; Supplementary Tables 1 and 2, Hunt et al. 2011. PubMed ID: 22200769). Functional analyses of this variant showed it impacted catalytical activity (Surolia et al. 2010. PubMed ID: 20555325; Chellappa et al. 2013. PubMed ID: 23308225). This variant is reported in 0.072% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-124519650-C-A), which may be too common to be causative of disease. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

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

Pathogenic

0.89

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.92

D;.;.

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.88

D;D;.

M_CAP

Pathogenic

0.40

MetaRNN

Pathogenic

0.90

D;D;D

MetaSVM

Pathogenic

0.92

MutationAssessor

Pathogenic

3.8

H;.;.

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-10

D;D;.

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

D;D;.

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.94

MVP

0.94

MPC

0.76

ClinPred

0.95

GERP RS

5.2

Varity_R

0.99

gMVP

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over