rs201877149

Positions:

• chr11-124638651-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2 O:1
• 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]

ACMG classification

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	UniProt
SIAE	NM_170601.5	c.1211T>C	p.Phe404Ser	missense_variant	9/10	ENST00000263593.8
SIAE	NM_001199922.2	c.1106T>C	p.Phe369Ser	missense_variant	11/12
SIAE	XM_047427132.1	c.638T>C	p.Phe213Ser	missense_variant	6/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIAE	ENST00000263593.8	c.1211T>C	p.Phe404Ser	missense_variant	9/10	1	NM_170601.5	P2
SIAE	ENST00000618733.4	c.1106T>C	p.Phe369Ser	missense_variant	11/12	1		A2
SIAE	ENST00000545756.5	c.1106T>C	p.Phe369Ser	missense_variant	10/11	5		A2

Frequencies

GnomAD3 genomes AF: 0.000217 AC: 33 AN: 152120 Hom.: 0 Cov.: 32

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

GnomAD3 exomes AF: 0.000171 AC: 43 AN: 251456 Hom.: 0 AF XY: 0.000162 AC XY: 22 AN XY: 135908

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 SAS 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.: 0 Cov.: 31 AF XY: 0.000103 AC XY: 75 AN XY: 727244

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00180

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000665

Gnomad4 OTH exome AF: 0.000265

GnomAD4 genome AF: 0.000217 AC: 33 AN: 152120 Hom.: 0 Cov.: 32 AF XY: 0.000256 AC XY: 19 AN XY: 74306

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000590

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000428 Hom.: 0

Bravo AF: 0.000219

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000107 AC: 13

EpiCase AF: 0.000218

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

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

Invitae

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Pathogenic	0.32
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	T;.;.
Eigen	Benign	0.070
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.77	T;T;.
M_CAP	Benign	0.041	D
MetaRNN	Uncertain	0.69	D;D;D
MetaSVM	Benign	-0.45	T
MutationAssessor	Uncertain	2.7	M;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.57	T
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	D
GERP RS		4.3
Varity_R		0.47
gMVP		0.86

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

LitVar

Other links and lift over

dbSNP: rs201877149; hg19: chr11-124508547;