chr11-124637047-A-C

Variant names:

• chr11-124637047-A-C
• rs747470616
• NM_170601.5:c.1476T>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_170601.5(SIAE):​c.1476T>G​(p.Cys492Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. C492C) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SIAE NM_170601.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.127
• Publications: 1 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.877

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIAE	NM_170601.5	c.1476T>G	p.Cys492Trp	missense_variant	Exon 10 of 10	ENST00000263593.8	NP_733746.1
SIAE	NM_001199922.2	c.1371T>G	p.Cys457Trp	missense_variant	Exon 12 of 12		NP_001186851.1
SIAE	XM_047427132.1	c.903T>G	p.Cys301Trp	missense_variant	Exon 7 of 7		XP_047283088.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIAE	ENST00000263593.8	c.1476T>G	p.Cys492Trp	missense_variant	Exon 10 of 10	1	NM_170601.5	ENSP00000263593.3
SIAE	ENST00000618733.4	c.1371T>G	p.Cys457Trp	missense_variant	Exon 12 of 12	1		ENSP00000478211.1
SIAE	ENST00000545756.5	c.1371T>G	p.Cys457Trp	missense_variant	Exon 11 of 11	5		ENSP00000437877.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.69	D;.;.
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.062
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.79	T;T;.
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.88	D;D;D
MetaSVM	Uncertain	0.39	D
MutationAssessor	Pathogenic	3.4	M;.;.
PhyloP100		0.13
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-9.6	D;D;.
REVEL	Uncertain	0.62
Sift	Pathogenic	0.0	D;D;.
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.79
MutPred		0.68		Loss of ubiquitination at K490 (P = 0.1664);.;.;
MVP		0.69
MPC		0.71
ClinPred		1.0	D
GERP RS		-0.74
Varity_R		0.94
gMVP		0.93
Mutation Taster		=26/74	disease causing

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

Other links and lift over

dbSNP: rs747470616; hg19: chr11-124506943;