19-51455668-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_014442.3(SIGLEC8):c.801T>A(p.Asn267Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,461,218 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.000014 ( 1 hom. )

Consequence

SIGLEC8
NM_014442.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -2.95

Variant links:

Genes affected

SIGLEC8 (HGNC:10877): (sialic acid binding Ig like lectin 8) Sialic acid-binding immunoglobulin (Ig)-like lectins, or SIGLECs (e.g., CD33 (MIM 159590)), are a family of type 1 transmembrane proteins each having a unique expression pattern, mostly in hemopoietic cells. SIGLEC8 is a member of the CD33-like subgroup of SIGLECs, which are localized to 19q13.3-q13.4 and have 2 conserved cytoplasmic tyrosine-based motifs: an immunoreceptor tyrosine-based inhibitory motif, or ITIM (see MIM 604964), and a motif homologous to one identified in signaling lymphocyte activation molecule (SLAM; MIM 603492) that mediates an association with SLAM-associated protein (SAP; MIM 300490) (summarized by Foussias et al., 2000 [PubMed 11095983]).[supplied by OMIM, May 2010]

SIGLEC8 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1

In a glycosylation_site N-linked (GlcNAc...) asparagine (size 0) in uniprot entity SIGL8_HUMAN

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.19337884).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SIGLEC8	NM_014442.3 linkuse as main transcript	c.801T>A	p.Asn267Lys	missense_variant	4/7	ENST00000321424.7
SIGLEC8	NM_001363548.1 linkuse as main transcript	c.522T>A	p.Asn174Lys	missense_variant	3/6
SIGLEC8	XM_011526734.3 linkuse as main transcript	c.768T>A	p.Asn256Lys	missense_variant	4/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIGLEC8	ENST00000321424.7 linkuse as main transcript	c.801T>A	p.Asn267Lys	missense_variant	4/7	1	NM_014442.3	P1	Q9NYZ4-1
SIGLEC8	ENST00000340550.5 linkuse as main transcript	c.522T>A	p.Asn174Lys	missense_variant	3/6	1			Q9NYZ4-2
SIGLEC8	ENST00000430817.5 linkuse as main transcript	c.474T>A	p.Asn158Lys	missense_variant	2/6	2
SIGLEC8	ENST00000597352.1 linkuse as main transcript	n.417T>A		non_coding_transcript_exon_variant	3/3	4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

250710

Hom.:

AF XY:

0.0000369

AC XY:

AN XY:

135512

show subpopulations

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:

0.000196

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1461218

Hom.:

Cov.:

AF XY:

0.0000206

AC XY:

AN XY:

726886

show subpopulations

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:

0.000186

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 27, 2023

The c.801T>A (p.N267K) alteration is located in exon 4 (coding exon 4) of the SIGLEC8 gene. This alteration results from a T to A substitution at nucleotide position 801, causing the asparagine (N) at amino acid position 267 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.60

Cadd

Benign

5.6

Dann

Benign

0.88

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0016

LIST_S2

Benign

0.72

T;T;T

M_CAP

Benign

0.0049

MetaRNN

Benign

0.19

T;T;T

MetaSVM

Benign

-0.61

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.42

PROVEAN

Pathogenic

-4.7

D;D;D

REVEL

Benign

0.091

Sift

Uncertain

0.012

D;D;D

Sift4G

Benign

0.068

T;D;D

Polyphen

0.97

D;P;D

Vest4

0.21

MutPred

0.43

.;Gain of ubiquitination at N267 (P = 0.0048);.;

MVP

0.44

MPC

0.45

ClinPred

0.83

GERP RS

-3.9

Varity_R

0.15

gMVP

0.082

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