19-51452612-T-G

Position:

• chr19-51452612-T-G

Variant summary

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

The NM_014442.3(SIGLEC8):​c.1267A>C​(p.Lys423Gln) 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: 31)
• Consequence: SIGLEC8 NM_014442.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.12

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=0.0625841).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIGLEC8	NM_014442.3	c.1267A>C	p.Lys423Gln	missense_variant	7/7	ENST00000321424.7
SIGLEC8	NM_001363548.1	c.988A>C	p.Lys330Gln	missense_variant	6/6
SIGLEC8	XM_011526734.3	c.1234A>C	p.Lys412Gln	missense_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIGLEC8	ENST00000321424.7	c.1267A>C	p.Lys423Gln	missense_variant	7/7	1	NM_014442.3	P1
SIGLEC8	ENST00000340550.5	c.988A>C	p.Lys330Gln	missense_variant	6/6	1
SIGLEC8	ENST00000430817.5	c.940A>C	p.Lys314Gln	missense_variant	5/6	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

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

Jun 04, 2024

The c.1267A>C (p.K423Q) alteration is located in exon 7 (coding exon 7) of the SIGLEC8 gene. This alteration results from a A to C substitution at nucleotide position 1267, causing the lysine (K) at amino acid position 423 to be replaced by a glutamine (Q). 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	0.096
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	0.17
DANN	Benign	0.16
DEOGEN2	Benign	0.0055	.;T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0028	N
LIST_S2	Benign	0.37	T;T;T
M_CAP	Benign	0.0025	T
MetaRNN	Benign	0.063	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	.;N;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.020	N;N;N
REVEL	Benign	0.044
Sift	Benign	0.55	T;T;T
Sift4G	Benign	0.60	T;T;T
Polyphen		0.76	P;B;P
Vest4		0.10
MutPred		0.34		.;Loss of ubiquitination at K423 (P = 0.0023);.;
MVP		0.34
MPC		0.091
ClinPred		0.17	T
GERP RS		-2.1
Varity_R		0.050
gMVP		0.063

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: rs1989392546; hg19: chr19-51955866;