19-51452510-G-A

Variant names:

• chr19-51452510-G-A
• NM_014442.3:c.1369C>T

Variant summary

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

The NM_014442.3(SIGLEC8):​c.1369C>T​(p.Pro457Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,454 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SIGLEC8 NM_014442.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0700

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12302968).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIGLEC8	NM_014442.3	c.1369C>T	p.Pro457Ser	missense_variant	Exon 7 of 7	ENST00000321424.7	NP_055257.2
SIGLEC8	NM_001363548.1	c.1090C>T	p.Pro364Ser	missense_variant	Exon 6 of 6		NP_001350477.1
SIGLEC8	XM_011526734.3	c.1336C>T	p.Pro446Ser	missense_variant	Exon 7 of 7		XP_011525036.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIGLEC8	ENST00000321424.7	c.1369C>T	p.Pro457Ser	missense_variant	Exon 7 of 7	1	NM_014442.3	ENSP00000321077.2
SIGLEC8	ENST00000340550.5	c.1090C>T	p.Pro364Ser	missense_variant	Exon 6 of 6	1		ENSP00000339448.4
SIGLEC8	ENST00000430817.5	c.1042C>T	p.Pro348Ser	missense_variant	Exon 5 of 6	2		ENSP00000389142.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455454 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 722906

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 08, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1369C>T (p.P457S) alteration is located in exon 7 (coding exon 7) of the SIGLEC8 gene. This alteration results from a C to T substitution at nucleotide position 1369, causing the proline (P) at amino acid position 457 to be replaced by a serine (S). 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	0.11
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	7.5
DANN	Uncertain	0.99
DEOGEN2	Benign	0.035	.;T;.
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.0063	N
LIST_S2	Benign	0.55	T;T;T
M_CAP	Benign	0.00071	T
MetaRNN	Benign	0.12	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	.;L;.
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-4.3	D;D;D
REVEL	Benign	0.051
Sift	Uncertain	0.020	D;T;T
Sift4G	Benign	0.19	T;T;T
Polyphen		0.81	P;D;D
Vest4		0.13
MutPred		0.52		.;Gain of relative solvent accessibility (P = 0.09);.;
MVP		0.37
MPC		0.088
ClinPred		0.72	D
GERP RS		-0.79
Varity_R		0.030
gMVP		0.098

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: chr19-51955764;