rs10409962

Positions:

• chr19-51457686-A-G

Variant summary

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

The NM_014442.3(SIGLEC8):​c.508T>C​(p.Ser170Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0977 in 1,606,140 control chromosomes in the GnomAD database, including 14,870 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 0.20 (5890 hom., cov: 31)
  • Exomes 𝑓: 0.086 (8980 hom.)
• Consequence: SIGLEC8 NM_014442.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.249

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=1.8909574E-4).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.498 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIGLEC8	NM_014442.3	c.508T>C	p.Ser170Pro	missense_variant	2/7	ENST00000321424.7
SIGLEC8	XM_011526734.3	c.475T>C	p.Ser159Pro	missense_variant	2/7
SIGLEC8	NM_001363548.1	c.454+248T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIGLEC8	ENST00000321424.7	c.508T>C	p.Ser170Pro	missense_variant	2/7	1	NM_014442.3	P1
SIGLEC8	ENST00000340550.5	c.454+248T>C		intron_variant		1
SIGLEC8	ENST00000430817.5	c.454+248T>C		intron_variant		2
SIGLEC8	ENST00000597352.1	n.124T>C		non_coding_transcript_exon_variant	1/3	4

Frequencies

GnomAD3 genomes AF: 0.204 AC: 31026 AN: 151874 Hom.: 5868 Cov.: 31

Gnomad AFR AF: 0.503

Gnomad AMI AF: 0.0592

Gnomad AMR AF: 0.137

Gnomad ASJ AF: 0.0750

Gnomad EAS AF: 0.110

Gnomad SAS AF: 0.0807

Gnomad FIN AF: 0.141

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.0723

Gnomad OTH AF: 0.200

GnomAD3 exomes AF: 0.116 AC: 28041 AN: 241486 Hom.: 3016 AF XY: 0.107 AC XY: 13949 AN XY: 130378

Gnomad AFR exome AF: 0.510

Gnomad AMR exome AF: 0.0892

Gnomad ASJ exome AF: 0.0777

Gnomad EAS exome AF: 0.116

Gnomad SAS exome AF: 0.0820

Gnomad FIN exome AF: 0.138

Gnomad NFE exome AF: 0.0749

Gnomad OTH exome AF: 0.0996

GnomAD4 exome AF: 0.0865 AC: 125773 AN: 1454148 Hom.: 8980 Cov.: 32 AF XY: 0.0843 AC XY: 60944 AN XY: 723080

Gnomad4 AFR exome AF: 0.514

Gnomad4 AMR exome AF: 0.0933

Gnomad4 ASJ exome AF: 0.0711

Gnomad4 EAS exome AF: 0.110

Gnomad4 SAS exome AF: 0.0790

Gnomad4 FIN exome AF: 0.133

Gnomad4 NFE exome AF: 0.0699

Gnomad4 OTH exome AF: 0.109

GnomAD4 genome AF: 0.205 AC: 31107 AN: 151992 Hom.: 5890 Cov.: 31 AF XY: 0.204 AC XY: 15141 AN XY: 74282

Gnomad4 AFR AF: 0.504

Gnomad4 AMR AF: 0.137

Gnomad4 ASJ AF: 0.0750

Gnomad4 EAS AF: 0.111

Gnomad4 SAS AF: 0.0812

Gnomad4 FIN AF: 0.141

Gnomad4 NFE AF: 0.0723

Gnomad4 OTH AF: 0.204

Alfa AF: 0.0980 Hom.: 2934

Bravo AF: 0.217

TwinsUK AF: 0.0677 AC: 251

ALSPAC AF: 0.0669 AC: 258

ESP6500AA AF: 0.495 AC: 2183

ESP6500EA AF: 0.0714 AC: 614

ExAC AF: 0.119 AC: 14396

Asia WGS AF: 0.166 AC: 577 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.040
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.45
DANN	Benign	0.069
DEOGEN2	Benign	0.0024	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.00014	N
LIST_S2	Benign	0.037	T
MetaRNN	Benign	0.00019	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-2.0	N
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.26	T
PROVEAN	Benign	6.2	N
REVEL	Benign	0.031
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.015
MPC		0.096
ClinPred		0.0032	T
GERP RS		0.34
Varity_R		0.056
gMVP		0.071

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: rs10409962; hg19: chr19-51960940; COSMIC: COSV58472823;