19-51457655-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_014442.3(SIGLEC8):c.539C>A(p.Ala180Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,950 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SIGLEC8 NM_014442.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.164

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30543786).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIGLEC8	NM_014442.3	c.539C>A	p.Ala180Asp	missense_variant	2/7	ENST00000321424.7
SIGLEC8	XM_011526734.3	c.506C>A	p.Ala169Asp	missense_variant	2/7
SIGLEC8	NM_001363548.1	c.454+279C>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIGLEC8	ENST00000321424.7	c.539C>A	p.Ala180Asp	missense_variant	2/7	1	NM_014442.3	P1
SIGLEC8	ENST00000340550.5	c.454+279C>A		intron_variant		1
SIGLEC8	ENST00000430817.5	c.454+279C>A		intron_variant		2
SIGLEC8	ENST00000597352.1	n.155C>A		non_coding_transcript_exon_variant	1/3	4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458950 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 725690

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

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

Oct 13, 2023

The c.539C>A (p.A180D) alteration is located in exon 2 (coding exon 2) of the SIGLEC8 gene. This alteration results from a C to A substitution at nucleotide position 539, causing the alanine (A) at amino acid position 180 to be replaced by an aspartic acid (D). 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	0.22
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.69
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Benign	0.060	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.0011	T
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Pathogenic	3.2	M
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Benign	0.063
Sift	Benign	0.071	T
Sift4G	Uncertain	0.050	T
Polyphen		0.89	P
Vest4		0.14
MutPred		0.68		Loss of sheet (P = 0.0357);
MVP		0.31
MPC		0.45
ClinPred		0.95	D
GERP RS		0.49
Varity_R		0.28
gMVP		0.13

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: chr19-51960909;