11-124636988-T-A

Variant names:

• chr11-124636988-T-A
• rs1942754853
• NM_170601.5:c.1535A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_170601.5(SIAE):​c.1535A>T​(p.Asp512Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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: 0.0000014 (0 hom.)
• Consequence: SIAE NM_170601.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.484
• Publications: 0 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15753326).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIAE	NM_170601.5	c.1535A>T	p.Asp512Val	missense_variant	Exon 10 of 10	ENST00000263593.8	NP_733746.1
SIAE	NM_001199922.2	c.1430A>T	p.Asp477Val	missense_variant	Exon 12 of 12		NP_001186851.1
SIAE	XM_047427132.1	c.962A>T	p.Asp321Val	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.1535A>T	p.Asp512Val	missense_variant	Exon 10 of 10	1	NM_170601.5	ENSP00000263593.3
SIAE	ENST00000618733.4	c.1430A>T	p.Asp477Val	missense_variant	Exon 12 of 12	1		ENSP00000478211.1
SIAE	ENST00000545756.5	c.1430A>T	p.Asp477Val	missense_variant	Exon 11 of 11	5		ENSP00000437877.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461888 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Feb 17, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid with valine at codon 512 of the SIAE protein (p.Asp512Val). The aspartic acid residue is weakly conserved and there is a large physicochemical difference between aspartic acid and valine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with SIAE-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.049	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	11
DANN	Benign	0.93
DEOGEN2	Benign	0.15	T;.;.
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.66	T;T;.
M_CAP	Benign	0.077	D
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Uncertain	2.2	M;.;.
PhyloP100		0.48
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.4	N;N;.
REVEL	Benign	0.19
Sift	Uncertain	0.011	D;D;.
Sift4G	Uncertain	0.0090	D;D;D
Polyphen		0.25	B;.;.
Vest4		0.13
MutPred		0.56		Gain of sheet (P = 0.0221);.;.;
MVP		0.61
MPC		0.23
ClinPred		0.15	T
GERP RS		0.096
Varity_R		0.097
gMVP		0.73
Mutation Taster		=96/4	polymorphism

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: rs1942754853; hg19: chr11-124506884;