19-51457463-G-A

Position:

chr19-51457463-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_014442.3(SIGLEC8):c.731C>T(p.Ser244Phe) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000521 in 1,613,622 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 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 Benign (★★).

Frequency

Genomes: 𝑓 0.0029 ( 2 hom., cov: 31)

Exomes 𝑓: 0.00027 ( 3 hom. )

Consequence

SIGLEC8
NM_014442.3 missense, splice_region

Scores

Splicing: ADA: 0.2457

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.533

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 Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013482302).

BP6

Variant 19-51457463-G-A is Benign according to our data. Variant chr19-51457463-G-A is described in ClinVar as [Benign]. Clinvar id is 716482.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SIGLEC8	NM_014442.3 linkuse as main transcript	c.731C>T	p.Ser244Phe	missense_variant, splice_region_variant	2/7	ENST00000321424.7
SIGLEC8	XM_011526734.3 linkuse as main transcript	c.698C>T	p.Ser233Phe	missense_variant, splice_region_variant	2/7
SIGLEC8	NM_001363548.1 linkuse as main transcript	c.455-232C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIGLEC8	ENST00000321424.7 linkuse as main transcript	c.731C>T	p.Ser244Phe	missense_variant, splice_region_variant	2/7	1	NM_014442.3	P1	Q9NYZ4-1
SIGLEC8	ENST00000340550.5 linkuse as main transcript	c.455-232C>T		intron_variant		1			Q9NYZ4-2
SIGLEC8	ENST00000430817.5 linkuse as main transcript	c.454+471C>T		intron_variant		2
SIGLEC8	ENST00000597352.1 linkuse as main transcript	n.347C>T		splice_region_variant, non_coding_transcript_exon_variant	1/3	4

Frequencies

GnomAD3 genomes

AF:

0.00286

AC:

435

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00983

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00157

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:

0.0000147

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000706

AC:

177

AN:

250884

Hom.:

AF XY:

0.000531

AC XY:

AN XY:

135596

show subpopulations

Gnomad AFR exome

AF:

0.00960

Gnomad AMR exome

AF:

0.000347

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000353

Gnomad OTH exome

AF:

0.000654

GnomAD4 exome

AF:

0.000270

AC:

395

AN:

1461372

Hom.:

Cov.:

AF XY:

0.000213

AC XY:

155

AN XY:

727026

show subpopulations

Gnomad4 AFR exome

AF:

0.00887

Gnomad4 AMR exome

AF:

0.000559

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.00108

GnomAD4 genome

AF:

0.00293

AC:

446

AN:

152250

Hom.:

Cov.:

AF XY:

0.00277

AC XY:

206

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.0101

Gnomad4 AMR

AF:

0.00157

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000482

Hom.:

Bravo

AF:

0.00315

ESP6500AA

AF:

0.0109

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000865

AC:

105

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 13, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.049

Eigen

Benign

-0.0051

Eigen_PC

Benign

-0.27

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.27

MetaRNN

Benign

0.013

MetaSVM

Benign

-0.37

MutationAssessor

Pathogenic

3.3

MutationTaster

Benign

0.97

D;D;N

PrimateAI

Benign

0.39

PROVEAN

Pathogenic

-5.1

REVEL

Benign

0.19

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

0.99

Vest4

0.21

MVP

0.76

MPC

0.44

ClinPred

0.095

GERP RS

1.6

Varity_R

0.16

gMVP

0.11

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.25

dbscSNV1_RF

Benign

0.34

SpliceAI score (max)

0.010

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