19-51455483-C-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_014442.3(SIGLEC8):c.986G>A(p.Arg329Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000191 in 1,614,012 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00020 ( 0 hom. )

Consequence

SIGLEC8
NM_014442.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.66

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.03359577).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIGLEC8	NM_014442.3 link	c.986G>A	p.Arg329Gln	missense_variant	Exon 4 of 7	ENST00000321424.7	NP_055257.2	Q9NYZ4-1
SIGLEC8	NM_001363548.1 link	c.707G>A	p.Arg236Gln	missense_variant	Exon 3 of 6		NP_001350477.1
SIGLEC8	XM_011526734.3 link	c.953G>A	p.Arg318Gln	missense_variant	Exon 4 of 7		XP_011525036.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SIGLEC8	ENST00000321424.7 link	c.986G>A	p.Arg329Gln	missense_variant	Exon 4 of 7	1	NM_014442.3	ENSP00000321077.2	Q9NYZ4-1
SIGLEC8	ENST00000340550.5 link	c.707G>A	p.Arg236Gln	missense_variant	Exon 3 of 6	1		ENSP00000339448.4	Q9NYZ4-2
SIGLEC8	ENST00000430817.5 link	c.659G>A	p.Arg220Gln	missense_variant	Exon 2 of 6	2		ENSP00000389142.1	C9JT30
SIGLEC8	ENST00000597352.1 link	n.*13G>A		downstream_gene_variant		4

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000175

AC:

AN:

251166

Hom.:

AF XY:

0.000162

AC XY:

AN XY:

135784

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000489

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000299

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000201

AC:

294

AN:

1461836

Hom.:

Cov.:

AF XY:

0.000183

AC XY:

133

AN XY:

727214

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000227

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000251

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000920

AC:

AN:

152176

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000193

Hom.:

Bravo

AF:

0.000136

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000239

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000237

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Feb 09, 2025

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.67

DANN

Benign

0.44

DEOGEN2

Benign

0.0023

.;T;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.0024

LIST_S2

Benign

0.17

T;T;T

M_CAP

Benign

0.00093

MetaRNN

Benign

0.034

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.47

.;N;.

PrimateAI

Benign

0.23

PROVEAN

Benign

0.22

N;N;N

REVEL

Benign

0.0090

Sift

Benign

0.80

T;T;T

Sift4G

Benign

0.84

T;T;T

Polyphen

0.47

P;B;P

Vest4

0.076

MVP

0.16

MPC

0.12

ClinPred

0.024

GERP RS

-1.6

Varity_R

0.029

gMVP

0.10

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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