rs36489

Variant names:

• chr19-51450840-A-G
• rs36489
• NM_014442.3:c.*1539T>C

Your query was ambiguous. Multiple possible variants found:

• chr19-51450840-A-G
• chr19-51450840-A-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014442.3(SIGLEC8):​c.*1539T>C variant causes a downstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.187 in 152,152 control chromosomes in the GnomAD database, including 3,050 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.19 (3050 hom., cov: 32)
  • Exomes 𝑓: 0.50 (0 hom.)
• Consequence: SIGLEC8 NM_014442.3 downstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.874
• Publications: 4 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.02).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.452 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014442.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIGLEC8	NM_014442.3	MANE Select	c.*1539T>C		downstream_gene	N/A	NP_055257.2	Q9NYZ4-1
	SIGLEC8	NM_001363548.1		c.*1539T>C		downstream_gene	N/A	NP_001350477.1	Q9NYZ4-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIGLEC8	ENST00000321424.7	TSL:1 MANE Select	c.*1539T>C		downstream_gene	N/A	ENSP00000321077.2	Q9NYZ4-1
	SIGLEC8	ENST00000960611.1		c.*1539T>C		downstream_gene	N/A	ENSP00000630670.1
	SIGLEC8	ENST00000960610.1		c.*1539T>C		downstream_gene	N/A	ENSP00000630669.1

Frequencies

GnomAD3 genomes AF: 0.187 AC: 28398 AN: 152032 Hom.: 3051 Cov.: 32

Gnomad AFR AF: 0.149

Gnomad AMI AF: 0.205

Gnomad AMR AF: 0.148

Gnomad ASJ AF: 0.139

Gnomad EAS AF: 0.467

Gnomad SAS AF: 0.226

Gnomad FIN AF: 0.212

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.193

Gnomad OTH AF: 0.174

GnomAD4 exome AF: 0.500 AC: 1 AN: 2 Hom.: 0 Cov.: 0 AF XY: 0.500 AC XY: 1 AN XY: 2

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.500 AC: 1 AN: 2

Other (OTH) AC: 0 AN: 0

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.187 AC: 28395 AN: 152150 Hom.: 3050 Cov.: 32 AF XY: 0.189 AC XY: 14029 AN XY: 74380

African (AFR) AF: 0.149 AC: 6179 AN: 41514

American (AMR) AF: 0.148 AC: 2256 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.139 AC: 484 AN: 3472

East Asian (EAS) AF: 0.468 AC: 2416 AN: 5166

South Asian (SAS) AF: 0.227 AC: 1095 AN: 4822

European-Finnish (FIN) AF: 0.212 AC: 2241 AN: 10586

Middle Eastern (MID) AF: 0.180 AC: 53 AN: 294

European-Non Finnish (NFE) AF: 0.193 AC: 13116 AN: 67978

Other (OTH) AF: 0.174 AC: 368 AN: 2114

Alfa AF: 0.188 Hom.: 11404

Bravo AF: 0.180

Asia WGS AF: 0.316 AC: 1098 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.0
DANN	Benign	0.49
PhyloP100		-0.87
Mutation Taster		=99/1	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs36489; hg19: chr19-51954094;