chr19-51455420-G-A

Position:

chr19-51455420-G-A

Variant summary

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

The NM_014442.3(SIGLEC8):c.1049C>T(p.Thr350Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000607 in 1,613,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000062 ( 0 hom. )

Consequence

SIGLEC8
NM_014442.3 missense, splice_region

Scores

Splicing: ADA: 0.1637

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0600

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09877661).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SIGLEC8	NM_014442.3 linkuse as main transcript	c.1049C>T	p.Thr350Ile	missense_variant, splice_region_variant	4/7	ENST00000321424.7
SIGLEC8	NM_001363548.1 linkuse as main transcript	c.770C>T	p.Thr257Ile	missense_variant, splice_region_variant	3/6
SIGLEC8	XM_011526734.3 linkuse as main transcript	c.1016C>T	p.Thr339Ile	missense_variant, splice_region_variant	4/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIGLEC8	ENST00000321424.7 linkuse as main transcript	c.1049C>T	p.Thr350Ile	missense_variant, splice_region_variant	4/7	1	NM_014442.3	P1	Q9NYZ4-1
SIGLEC8	ENST00000340550.5 linkuse as main transcript	c.770C>T	p.Thr257Ile	missense_variant, splice_region_variant	3/6	1			Q9NYZ4-2
SIGLEC8	ENST00000430817.5 linkuse as main transcript	c.722C>T	p.Thr241Ile	missense_variant, splice_region_variant	2/6	2

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000762

AC:

AN:

249444

Hom.:

AF XY:

0.0000889

AC XY:

AN XY:

134962

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.000175

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000981

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000616

AC:

AN:

1461346

Hom.:

Cov.:

AF XY:

0.0000674

AC XY:

AN XY:

726970

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000202

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000693

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000525

AC:

AN:

152346

Hom.:

Cov.:

AF XY:

0.0000805

AC XY:

AN XY:

74512

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000564

Hom.:

Bravo

AF:

0.0000453

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000906

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000297

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

Aug 13, 2021

The c.1049C>T (p.T350I) alteration is located in exon 4 (coding exon 4) of the SIGLEC8 gene. This alteration results from a C to T substitution at nucleotide position 1049, causing the threonine (T) at amino acid position 350 to be replaced by an isoleucine (I). 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

0.12

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.64

CADD

Benign

8.2

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0033

.;T;.

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.92

FATHMM_MKL

Benign

0.0074

LIST_S2

Benign

0.70

T;T;T

M_CAP

Benign

0.0029

MetaRNN

Benign

0.099

T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.6

.;L;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-2.6

D;N;N

REVEL

Benign

0.066

Sift

Benign

0.058

T;D;D

Sift4G

Benign

0.23

T;T;T

Polyphen

0.98

D;P;D

Vest4

0.15

MVP

0.66

MPC

0.24

ClinPred

0.29

GERP RS

-1.4

Varity_R

0.040

gMVP

0.081

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.16

dbscSNV1_RF

Benign

0.36

SpliceAI score (max)

0.13

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