rs146563540

Variant names:

• chr19-51454290-C-A
• rs146563540
• NM_014442.3:c.1174G>T

Your query was ambiguous. Multiple possible variants found:

• chr19-51454290-C-A
• chr19-51454290-C-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.1174G>T​(p.Ala392Ser) 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A392T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SIGLEC8 NM_014442.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.34

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=0.08169049).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIGLEC8	NM_014442.3	c.1174G>T	p.Ala392Ser	missense_variant	Exon 6 of 7	ENST00000321424.7	NP_055257.2
SIGLEC8	NM_001363548.1	c.895G>T	p.Ala299Ser	missense_variant	Exon 5 of 6		NP_001350477.1
SIGLEC8	XM_011526734.3	c.1141G>T	p.Ala381Ser	missense_variant	Exon 6 of 7		XP_011525036.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIGLEC8	ENST00000321424.7	c.1174G>T	p.Ala392Ser	missense_variant	Exon 6 of 7	1	NM_014442.3	ENSP00000321077.2
SIGLEC8	ENST00000340550.5	c.895G>T	p.Ala299Ser	missense_variant	Exon 5 of 6	1		ENSP00000339448.4
SIGLEC8	ENST00000430817.5	c.847G>T	p.Ala283Ser	missense_variant	Exon 4 of 6	2		ENSP00000389142.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.10
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0033	.;T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0018	N
LIST_S2	Benign	0.44	T;T;T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.082	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.2	.;M;.
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.6	N;N;N
REVEL	Benign	0.041
Sift	Benign	0.20	T;T;T
Sift4G	Benign	0.12	T;T;D
Polyphen		0.54	P;B;P
Vest4		0.13
MutPred		0.22		.;Gain of phosphorylation at A392 (P = 0.0551);.;
MVP		0.51
MPC		0.20
ClinPred		0.16	T
GERP RS		-3.6
Varity_R		0.049
gMVP		0.051

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

LitVar

Other links and lift over

dbSNP: rs146563540; hg19: chr19-51957544;