11-124636979-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_170601.5(SIAE):c.1544C>T(p.Pro515Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000015 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: SIAE NM_170601.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.16

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17770916).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIAE	NM_170601.5	c.1544C>T	p.Pro515Leu	missense_variant	10/10	ENST00000263593.8
SIAE	NM_001199922.2	c.1439C>T	p.Pro480Leu	missense_variant	12/12
SIAE	XM_047427132.1	c.971C>T	p.Pro324Leu	missense_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIAE	ENST00000263593.8	c.1544C>T	p.Pro515Leu	missense_variant	10/10	1	NM_170601.5	P2
SIAE	ENST00000618733.4	c.1439C>T	p.Pro480Leu	missense_variant	12/12	1		A2
SIAE	ENST00000545756.5	c.1439C>T	p.Pro480Leu	missense_variant	11/11	5		A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251458 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135900

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000150 AC: 22 AN: 1461892 Hom.: 0 Cov.: 30 AF XY: 0.0000206 AC XY: 15 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000255

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 20, 2021

The c.1544C>T (p.P515L) alteration is located in exon 10 (coding exon 10) of the SIAE gene. This alteration results from a C to T substitution at nucleotide position 1544, causing the proline (P) at amino acid position 515 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 06, 2022

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 1469979). This variant has not been reported in the literature in individuals affected with SIAE-related conditions. This variant is present in population databases (rs762731994, gnomAD 0.01%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 515 of the SIAE protein (p.Pro515Leu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	14
Dann	Uncertain	0.98
DEOGEN2	Benign	0.20	T;.;.
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.50	T;T;.
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.18	T;T;T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	1.5	L;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.5	N;N;.
REVEL	Benign	0.23
Sift	Uncertain	0.010	D;D;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.0010	B;.;.
Vest4		0.15
MutPred		0.37		Gain of catalytic residue at P515 (P = 0.0065);.;.;
MVP		0.68
MPC		0.19
ClinPred		0.13	T
GERP RS		4.0
Varity_R		0.039
gMVP		0.37

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: rs762731994; hg19: chr11-124506875;