chr19-51458003-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_014442.3(SIGLEC8):c.385G>C(p.Gly129Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00184 in 1,614,162 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00076 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0020 ( 7 hom. )

Consequence

SIGLEC8
NM_014442.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.743

Publications

4 publications found

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 was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.024586916).

BS2

High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIGLEC8	NM_014442.3 link	c.385G>C	p.Gly129Arg	missense_variant	Exon 1 of 7	ENST00000321424.7	NP_055257.2	Q9NYZ4-1
SIGLEC8	NM_001363548.1 link	c.385G>C	p.Gly129Arg	missense_variant	Exon 1 of 6		NP_001350477.1
SIGLEC8	XM_011526734.3 link	c.385G>C	p.Gly129Arg	missense_variant	Exon 1 of 7		XP_011525036.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SIGLEC8	ENST00000321424.7 link	c.385G>C	p.Gly129Arg	missense_variant	Exon 1 of 7	1	NM_014442.3	ENSP00000321077.2	Q9NYZ4-1
SIGLEC8	ENST00000340550.5 link	c.385G>C	p.Gly129Arg	missense_variant	Exon 1 of 6	1		ENSP00000339448.4	Q9NYZ4-2
SIGLEC8	ENST00000430817.5 link	c.385G>C	p.Gly129Arg	missense_variant	Exon 1 of 6	2		ENSP00000389142.1	C9JT30
SIGLEC8	ENST00000597352.1 link	n.-194G>C		upstream_gene_variant		4

Frequencies

GnomAD3 genomes

AF:

0.000762

AC:

116

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000604

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00129

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000688

AC:

173

AN:

251484

AF XY:

0.000736

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000416

Gnomad NFE exome

AF:

0.00132

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.00196

AC:

2862

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00196

AC XY:

1422

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.000269

AC:

AN:

33480

American (AMR)

AF:

0.0000894

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000281

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00245

AC:

2724

AN:

1112008

Other (OTH)

AF:

0.00180

AC:

109

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

161

322

484

645

806

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

240

360

480

600

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000755

AC:

115

AN:

152272

Hom.:

Cov.:

AF XY:

0.000578

AC XY:

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.000602

AC:

AN:

41538

American (AMR)

AF:

0.0000653

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.000189

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00128

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00127

Hom.:

Bravo

AF:

0.000839

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00337

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00163

AC:

ExAC

AF:

0.000700

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00136

EpiControl

AF:

0.00142

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 09, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.385G>C (p.G129R) alteration is located in exon 1 (coding exon 1) of the SIGLEC8 gene. This alteration results from a G to C substitution at nucleotide position 385, causing the glycine (G) at amino acid position 129 to be replaced by an arginine (R). 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

Pathogenic

0.63

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.065

.;T;.

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.54

FATHMM_MKL

Benign

0.029

LIST_S2

Benign

0.46

T;T;T

M_CAP

Benign

0.0049

MetaRNN

Benign

0.025

T;T;T

MetaSVM

Benign

-0.67

MutationAssessor

Uncertain

2.4

.;M;M

PhyloP100

0.74

PrimateAI

Benign

0.38

PROVEAN

Pathogenic

-6.7

D;D;D

REVEL

Benign

0.097

Sift

Benign

0.043

D;D;T

Sift4G

Uncertain

0.025

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.27

MutPred

0.56

Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);

MVP

0.82

MPC

0.37

ClinPred

0.096

GERP RS

1.5

PromoterAI

-0.022

Neutral

(source)

Varity_R

0.23

gMVP

0.22

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over