Variant chr19-51452531-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_014442.3(SIGLEC8):c.1348C>T(p.Leu450Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,447,012 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

SIGLEC8
NM_014442.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0160

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:

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ACMG classification

Classification made for transcript

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=0.18103552).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SIGLEC8	NM_014442.3 linkuse as main transcript	c.1348C>T	p.Leu450Phe	missense_variant	7/7	ENST00000321424.7	NP_055257.2	Q9NYZ4-1
SIGLEC8	NM_001363548.1 linkuse as main transcript	c.1069C>T	p.Leu357Phe	missense_variant	6/6		NP_001350477.1
SIGLEC8	XM_011526734.3 linkuse as main transcript	c.1315C>T	p.Leu439Phe	missense_variant	7/7		XP_011525036.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SIGLEC8	ENST00000321424.7 linkuse as main transcript	c.1348C>T	p.Leu450Phe	missense_variant	7/7	1	NM_014442.3	ENSP00000321077.2	Q9NYZ4-1
SIGLEC8	ENST00000340550.5 linkuse as main transcript	c.1069C>T	p.Leu357Phe	missense_variant	6/6	1		ENSP00000339448.4	Q9NYZ4-2
SIGLEC8	ENST00000430817.5 linkuse as main transcript	c.1021C>T	p.Leu341Phe	missense_variant	5/6	2		ENSP00000389142.1	C9JT30

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.91e-7

AC:

AN:

1447012

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

716376

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

EpiCase

AF:

0.0000547

EpiControl

AF:

0.00

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

Sep 11, 2024

The c.1348C>T (p.L450F) alteration is located in exon 7 (coding exon 7) of the SIGLEC8 gene. This alteration results from a C to T substitution at nucleotide position 1348, causing the leucine (L) at amino acid position 450 to be replaced by a phenylalanine (F). 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

Benign

0.16

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.68

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.050

.;T;.

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.0087

LIST_S2

Benign

0.84

T;T;T

M_CAP

Benign

0.0012

MetaRNN

Benign

0.18

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.2

.;M;.

PrimateAI

Uncertain

0.49

PROVEAN

Uncertain

-2.7

D;D;D

REVEL

Benign

0.037

Sift

Uncertain

0.0070

D;T;D

Sift4G

Benign

0.081

T;T;D

Polyphen

0.97

D;D;D

Vest4

0.094

MutPred

0.50

.;Gain of sheet (P = 0.0344);.;

MVP

0.19

MPC

0.36

ClinPred

0.83

GERP RS

-0.80

Varity_R

0.086

gMVP

0.065

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over