19-51455613-T-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_014442.3(SIGLEC8):c.856A>G(p.Asn286Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000459 in 1,613,942 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000047 (0 hom.)
• Consequence: SIGLEC8 NM_014442.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.89

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 -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.013117224).
• BP6: Variant 19-51455613-T-C is Benign according to our data. Variant chr19-51455613-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 2510948.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIGLEC8	NM_014442.3	c.856A>G	p.Asn286Asp	missense_variant	4/7	ENST00000321424.7
SIGLEC8	NM_001363548.1	c.577A>G	p.Asn193Asp	missense_variant	3/6
SIGLEC8	XM_011526734.3	c.823A>G	p.Asn275Asp	missense_variant	4/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIGLEC8	ENST00000321424.7	c.856A>G	p.Asn286Asp	missense_variant	4/7	1	NM_014442.3	P1
SIGLEC8	ENST00000340550.5	c.577A>G	p.Asn193Asp	missense_variant	3/6	1
SIGLEC8	ENST00000430817.5	c.529A>G	p.Asn177Asp	missense_variant	2/6	2
SIGLEC8	ENST00000597352.1	n.472A>G		non_coding_transcript_exon_variant	3/3	4

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152188 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000995 AC: 25 AN: 251276 Hom.: 0 AF XY: 0.0000884 AC XY: 12 AN XY: 135804

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000492

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000465 AC: 68 AN: 1461754 Hom.: 0 Cov.: 32 AF XY: 0.0000481 AC XY: 35 AN XY: 727188

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000380

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000405

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152188 Hom.: 0 Cov.: 31 AF XY: 0.0000403 AC XY: 3 AN XY: 74350

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000113 Hom.: 0

Bravo AF: 0.0000756

ExAC AF: 0.0000988 AC: 12

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 23, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.91
Cadd	Benign	0.0050
Dann	Benign	0.21
Eigen	Benign	-2.3
Eigen_PC	Benign	-2.3
FATHMM_MKL	Benign	0.00031	N
LIST_S2	Benign	0.068	T;T;T
M_CAP	Benign	0.00064	T
MetaRNN	Benign	0.013	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	2.2	N;N;N
REVEL	Benign	0.041
Sift	Benign	1.0	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0030	B;B;B
Vest4		0.079
MVP		0.16
MPC		0.087
ClinPred		0.034	T
GERP RS		-4.4
Varity_R		0.026
gMVP		0.045

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: rs769416918; hg19: chr19-51958867;