rs3829659

Positions:

• chr19-51454302-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014442.3(SIGLEC8):​c.1162A>G​(p.Arg388Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.264 in 1,612,780 control chromosomes in the GnomAD database, including 59,898 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.33 (9635 hom., cov: 31)
  • Exomes 𝑓: 0.26 (50263 hom.)
• Consequence: SIGLEC8 NM_014442.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.757

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.0978535E-4).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.52 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SIGLEC8	NM_014442.3	c.1162A>G	p.Arg388Gly	missense_variant	6/7	ENST00000321424.7	NP_055257.2
SIGLEC8	NM_001363548.1	c.883A>G	p.Arg295Gly	missense_variant	5/6		NP_001350477.1
SIGLEC8	XM_011526734.3	c.1129A>G	p.Arg377Gly	missense_variant	6/7		XP_011525036.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SIGLEC8	ENST00000321424.7	c.1162A>G	p.Arg388Gly	missense_variant	6/7	1	NM_014442.3	ENSP00000321077	P1
SIGLEC8	ENST00000340550.5	c.883A>G	p.Arg295Gly	missense_variant	5/6	1		ENSP00000339448
SIGLEC8	ENST00000430817.5	c.835A>G	p.Arg279Gly	missense_variant	4/6	2		ENSP00000389142

Frequencies

GnomAD3 genomes AF: 0.331 AC: 50345 AN: 151936 Hom.: 9605 Cov.: 31

Gnomad AFR AF: 0.525

Gnomad AMI AF: 0.262

Gnomad AMR AF: 0.249

Gnomad ASJ AF: 0.193

Gnomad EAS AF: 0.220

Gnomad SAS AF: 0.244

Gnomad FIN AF: 0.350

Gnomad MID AF: 0.323

Gnomad NFE AF: 0.252

Gnomad OTH AF: 0.316

GnomAD3 exomes AF: 0.264 AC: 66284 AN: 251448 Hom.: 9707 AF XY: 0.258 AC XY: 35113 AN XY: 135898

Gnomad AFR exome AF: 0.530

Gnomad AMR exome AF: 0.207

Gnomad ASJ exome AF: 0.197

Gnomad EAS exome AF: 0.213

Gnomad SAS exome AF: 0.235

Gnomad FIN exome AF: 0.347

Gnomad NFE exome AF: 0.249

Gnomad OTH exome AF: 0.258

GnomAD4 exome AF: 0.257 AC: 374952 AN: 1460726 Hom.: 50263 Cov.: 37 AF XY: 0.254 AC XY: 184763 AN XY: 726672

Gnomad4 AFR exome AF: 0.541

Gnomad4 AMR exome AF: 0.215

Gnomad4 ASJ exome AF: 0.190

Gnomad4 EAS exome AF: 0.270

Gnomad4 SAS exome AF: 0.235

Gnomad4 FIN exome AF: 0.342

Gnomad4 NFE exome AF: 0.248

Gnomad4 OTH exome AF: 0.263

GnomAD4 genome AF: 0.332 AC: 50430 AN: 152054 Hom.: 9635 Cov.: 31 AF XY: 0.332 AC XY: 24659 AN XY: 74318

Gnomad4 AFR AF: 0.526

Gnomad4 AMR AF: 0.248

Gnomad4 ASJ AF: 0.193

Gnomad4 EAS AF: 0.221

Gnomad4 SAS AF: 0.245

Gnomad4 FIN AF: 0.350

Gnomad4 NFE AF: 0.252

Gnomad4 OTH AF: 0.323

Alfa AF: 0.268 Hom.: 1948

Bravo AF: 0.333

TwinsUK AF: 0.243 AC: 902

ALSPAC AF: 0.241 AC: 929

ESP6500AA AF: 0.537 AC: 2365

ESP6500EA AF: 0.243 AC: 2089

ExAC AF: 0.267 AC: 32355

Asia WGS AF: 0.303 AC: 1057 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	13
DANN	Benign	0.95
DEOGEN2	Benign	0.14	.;T;.
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.0056	N
LIST_S2	Benign	0.65	T;T;T
MetaRNN	Benign	0.00011	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Pathogenic	3.2	.;M;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.36	T
PROVEAN	Pathogenic	-5.0	D;D;D
REVEL	Benign	0.099
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		1.0	D;P;P
Vest4		0.10
MPC		0.49
ClinPred		0.076	T
GERP RS		-0.073
Varity_R		0.092
gMVP		0.16

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: rs3829659; hg19: chr19-51957556; COSMIC: COSV58472817; COSMIC: COSV58472817;