rs36495

Positions:

• chr19-51456971-A-G
• chr19-51456971-A-T

Variant summary

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

The NM_014442.3(SIGLEC8):​c.781+213T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.382 in 151,962 control chromosomes in the GnomAD database, including 13,233 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 0.38 (13233 hom., cov: 31)
• Consequence: SIGLEC8 NM_014442.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.08

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 (BayesDel_noAF=-0.99).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.621 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SIGLEC8	NM_014442.3	c.781+213T>C		intron_variant		ENST00000321424.7	NP_055257.2
SIGLEC8	NM_001363548.1	c.502+213T>C		intron_variant			NP_001350477.1
SIGLEC8	XM_011526734.3	c.748+213T>C		intron_variant			XP_011525036.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SIGLEC8	ENST00000321424.7	c.781+213T>C		intron_variant		1	NM_014442.3	ENSP00000321077	P1
SIGLEC8	ENST00000340550.5	c.502+213T>C		intron_variant		1		ENSP00000339448
SIGLEC8	ENST00000430817.5	c.454+963T>C		intron_variant		2		ENSP00000389142
SIGLEC8	ENST00000597352.1	n.397+213T>C		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.382 AC: 57966 AN: 151844 Hom.: 13187 Cov.: 31

Gnomad AFR AF: 0.627

Gnomad AMI AF: 0.265

Gnomad AMR AF: 0.272

Gnomad ASJ AF: 0.210

Gnomad EAS AF: 0.578

Gnomad SAS AF: 0.300

Gnomad FIN AF: 0.355

Gnomad MID AF: 0.339

Gnomad NFE AF: 0.264

Gnomad OTH AF: 0.351

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.382 AC: 58061 AN: 151962 Hom.: 13233 Cov.: 31 AF XY: 0.382 AC XY: 28406 AN XY: 74272

Gnomad4 AFR AF: 0.628

Gnomad4 AMR AF: 0.271

Gnomad4 ASJ AF: 0.210

Gnomad4 EAS AF: 0.579

Gnomad4 SAS AF: 0.300

Gnomad4 FIN AF: 0.355

Gnomad4 NFE AF: 0.264

Gnomad4 OTH AF: 0.356

Alfa AF: 0.335 Hom.: 1232

Bravo AF: 0.387

Asia WGS AF: 0.471 AC: 1639 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.054
DANN	Benign	0.46

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: rs36495; hg19: chr19-51960225; COSMIC: COSV58476393;