19-51452558-C-T

Position:

• chr19-51452558-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_014442.3(SIGLEC8):​c.1321G>A​(p.Glu441Lys) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SIGLEC8 NM_014442.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.875

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06351566).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIGLEC8	NM_014442.3	c.1321G>A	p.Glu441Lys	missense_variant	7/7	ENST00000321424.7
SIGLEC8	NM_001363548.1	c.1042G>A	p.Glu348Lys	missense_variant	6/6
SIGLEC8	XM_011526734.3	c.1288G>A	p.Glu430Lys	missense_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIGLEC8	ENST00000321424.7	c.1321G>A	p.Glu441Lys	missense_variant	7/7	1	NM_014442.3	P1
SIGLEC8	ENST00000340550.5	c.1042G>A	p.Glu348Lys	missense_variant	6/6	1
SIGLEC8	ENST00000430817.5	c.994G>A	p.Glu332Lys	missense_variant	5/6	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

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 04, 2023

The c.1321G>A (p.E441K) alteration is located in exon 7 (coding exon 7) of the SIGLEC8 gene. This alteration results from a G to A substitution at nucleotide position 1321, causing the glutamic acid (E) at amino acid position 441 to be replaced by a lysine (K). 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	0.070
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	1.0
DANN	Benign	0.94
DEOGEN2	Benign	0.0068	.;T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0022	N
LIST_S2	Benign	0.38	T;T;T
M_CAP	Benign	0.00055	T
MetaRNN	Benign	0.064	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	.;L;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.2	N;N;N
REVEL	Benign	0.014
Sift	Benign	0.32	T;D;T
Sift4G	Benign	0.18	T;T;T
Polyphen		0.098	B;B;B
Vest4		0.16
MutPred		0.37		.;Gain of ubiquitination at E441 (P = 0.0011);.;
MVP		0.19
MPC		0.20
ClinPred		0.26	T
GERP RS		-4.2
Varity_R		0.051
gMVP		0.075

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: chr19-51955812;