19-51455603-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_014442.3(SIGLEC8):c.866C>A(p.Pro289His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P289S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SIGLEC8 NM_014442.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.62

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIGLEC8	NM_014442.3	c.866C>A	p.Pro289His	missense_variant	4/7	ENST00000321424.7
SIGLEC8	NM_001363548.1	c.587C>A	p.Pro196His	missense_variant	3/6
SIGLEC8	XM_011526734.3	c.833C>A	p.Pro278His	missense_variant	4/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIGLEC8	ENST00000321424.7	c.866C>A	p.Pro289His	missense_variant	4/7	1	NM_014442.3	P1
SIGLEC8	ENST00000340550.5	c.587C>A	p.Pro196His	missense_variant	3/6	1
SIGLEC8	ENST00000430817.5	c.539C>A	p.Pro180His	missense_variant	2/6	2
SIGLEC8	ENST00000597352.1	n.482C>A		non_coding_transcript_exon_variant	3/3	4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 28, 2023

The c.866C>A (p.P289H) alteration is located in exon 4 (coding exon 4) of the SIGLEC8 gene. This alteration results from a C to A substitution at nucleotide position 866, causing the proline (P) at amino acid position 289 to be replaced by a histidine (H). 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	Uncertain	0.49
BayesDel_addAF	Benign	-0.092	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	22
Dann	Uncertain	0.99
Eigen	Uncertain	0.44
Eigen_PC	Benign	0.12
FATHMM_MKL	Benign	0.18	N
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Benign	0.0015	T
MetaRNN	Uncertain	0.46	T;T;T
MetaSVM	Benign	-0.72	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-6.8	D;D;D
REVEL	Benign	0.090
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.35
MutPred		0.63		.;Gain of MoRF binding (P = 0.0516);.;
MVP		0.54
MPC		0.47
ClinPred		0.99	D
GERP RS		2.2
Varity_R		0.75
gMVP		0.30

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.

Other links and lift over

hg19: chr19-51958857;