19-51454696-A-G

Position:

• chr19-51454696-A-G

Variant summary

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

The NM_014442.3(SIGLEC8):​c.1136T>C​(p.Ile379Thr) 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: 0.635

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=0.13443393).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SIGLEC8	NM_014442.3	c.1136T>C	p.Ile379Thr	missense_variant	5/7	ENST00000321424.7	NP_055257.2
SIGLEC8	NM_001363548.1	c.857T>C	p.Ile286Thr	missense_variant	4/6		NP_001350477.1
SIGLEC8	XM_011526734.3	c.1103T>C	p.Ile368Thr	missense_variant	5/7		XP_011525036.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SIGLEC8	ENST00000321424.7	c.1136T>C	p.Ile379Thr	missense_variant	5/7	1	NM_014442.3	ENSP00000321077.2
SIGLEC8	ENST00000340550.5	c.857T>C	p.Ile286Thr	missense_variant	4/6	1		ENSP00000339448.4
SIGLEC8	ENST00000430817.5	c.809T>C	p.Ile270Thr	missense_variant	3/6	2		ENSP00000389142.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

Jul 16, 2024

The c.1136T>C (p.I379T) alteration is located in exon 5 (coding exon 5) of the SIGLEC8 gene. This alteration results from a T to C substitution at nucleotide position 1136, causing the isoleucine (I) at amino acid position 379 to be replaced by a threonine (T). 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	0.36
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	15
DANN	Benign	0.94
DEOGEN2	Benign	0.027	.;T;.
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.0094	N
LIST_S2	Benign	0.68	T;T;T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.7	.;L;.
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-3.0	D;N;D
REVEL	Benign	0.027
Sift	Uncertain	0.0050	D;D;D
Sift4G	Benign	0.10	T;T;D
Polyphen		0.87	P;B;P
Vest4		0.18
MutPred		0.48		.;Loss of stability (P = 0.0084);.;
MVP		0.46
MPC		0.12
ClinPred		0.35	T
GERP RS		2.3
Varity_R		0.12
gMVP		0.10

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: chr19-51957950;