Genetic Variant NM_014442.3:c.385G>A (chr19-51458003-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_014442.3(SIGLEC8):c.385G>A(p.Gly129Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,890 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. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SIGLEC8
NM_014442.3 missense

Scores

Clinical Significance

Not reported in ClinVar

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.33375502).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIGLEC8	NM_014442.3 link	c.385G>A	p.Gly129Arg	missense_variant	Exon 1 of 7	ENST00000321424.7	NP_055257.2	Q9NYZ4-1
SIGLEC8	NM_001363548.1 link	c.385G>A	p.Gly129Arg	missense_variant	Exon 1 of 6		NP_001350477.1
SIGLEC8	XM_011526734.3 link	c.385G>A	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>A	p.Gly129Arg	missense_variant	Exon 1 of 7	1	NM_014442.3	ENSP00000321077.2	Q9NYZ4-1
SIGLEC8	ENST00000340550.5 link	c.385G>A	p.Gly129Arg	missense_variant	Exon 1 of 6	1		ENSP00000339448.4	Q9NYZ4-2
SIGLEC8	ENST00000430817.5 link	c.385G>A	p.Gly129Arg	missense_variant	Exon 1 of 6	2		ENSP00000389142.1	C9JT30
SIGLEC8	ENST00000597352.1 link	n.-194G>A		upstream_gene_variant		4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112008

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.63

BayesDel_addAF

Benign

-0.14

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

0.023

LIST_S2

Benign

0.46

T;T;T

M_CAP

Benign

0.0049

MetaRNN

Benign

0.33

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

0.10

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

0.69

GERP RS

1.5

PromoterAI

-0.026

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over