19-51455522-G-A

Position:

• chr19-51455522-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014442.3(SIGLEC8):​c.947C>T​(p.Pro316Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SIGLEC8 NM_014442.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.412

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 (HGNC:):

ACMG classification

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=0.23689356).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SIGLEC8	NM_014442.3	c.947C>T	p.Pro316Leu	missense_variant	4/7	ENST00000321424.7	NP_055257.2
SIGLEC8	NM_001363548.1	c.668C>T	p.Pro223Leu	missense_variant	3/6		NP_001350477.1
SIGLEC8	XM_011526734.3	c.914C>T	p.Pro305Leu	missense_variant	4/7		XP_011525036.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SIGLEC8	ENST00000321424.7	c.947C>T	p.Pro316Leu	missense_variant	4/7	1	NM_014442.3	ENSP00000321077.2
SIGLEC8	ENST00000340550.5	c.668C>T	p.Pro223Leu	missense_variant	3/6	1		ENSP00000339448.4
SIGLEC8	ENST00000430817.5	c.620C>T	p.Pro207Leu	missense_variant	2/6	2		ENSP00000389142.1
SIGLEC8	ENST00000597352.1	n.563C>T		non_coding_transcript_exon_variant	3/3	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Aug 10, 2024

The c.947C>T (p.P316L) 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 947, causing the proline (P) at amino acid position 316 to be replaced by a leucine (L). 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	0.15
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	15
DANN	Benign	0.94
DEOGEN2	Benign	0.028	.;T;.
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.0066	N
LIST_S2	Benign	0.78	T;T;T
M_CAP	Benign	0.00099	T
MetaRNN	Benign	0.24	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	.;M;.
PrimateAI	Benign	0.41	T
PROVEAN	Pathogenic	-5.2	D;D;D
REVEL	Benign	0.035
Sift	Benign	0.090	T;D;T
Sift4G	Benign	0.078	T;D;D
Polyphen		0.82	P;P;D
Vest4		0.10
MutPred		0.68		.;Loss of disorder (P = 0.0455);.;
MVP		0.45
MPC		0.081
ClinPred		0.88	D
GERP RS		-0.055
Varity_R		0.084
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs1989468879; hg19: chr19-51958776;