19-51452586-A-C

Position:

• chr19-51452586-A-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_014442.3(SIGLEC8):​c.1293T>G​(p.Pro431=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00238 in 1,571,174 control chromosomes in the GnomAD database, including 69 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (31 hom., cov: 31)
  • Exomes 𝑓: 0.0013 (38 hom.)
• Consequence: SIGLEC8 NM_014442.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.43

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.04).
• BP6: Variant 19-51452586-A-C is Benign according to our data. Variant chr19-51452586-A-C is described in ClinVar as [Benign]. Clinvar id is 769047.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.43 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0129 (1955/151876) while in subpopulation AFR AF= 0.0443 (1835/41400). AF 95% confidence interval is 0.0426. There are 31 homozygotes in gnomad4. There are 928 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 31 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIGLEC8	NM_014442.3	c.1293T>G	p.Pro431=	synonymous_variant	7/7	ENST00000321424.7
SIGLEC8	NM_001363548.1	c.1014T>G	p.Pro338=	synonymous_variant	6/6
SIGLEC8	XM_011526734.3	c.1260T>G	p.Pro420=	synonymous_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIGLEC8	ENST00000321424.7	c.1293T>G	p.Pro431=	synonymous_variant	7/7	1	NM_014442.3	P1
SIGLEC8	ENST00000340550.5	c.1014T>G	p.Pro338=	synonymous_variant	6/6	1
SIGLEC8	ENST00000430817.5	c.966T>G	p.Pro322=	synonymous_variant	5/6	2

Frequencies

GnomAD3 genomes AF: 0.0129 AC: 1955 AN: 151758 Hom.: 31 Cov.: 31

Gnomad AFR AF: 0.0444

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00519

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.0125

GnomAD3 exomes AF: 0.00362 AC: 827 AN: 228606 Hom.: 23 AF XY: 0.00252 AC XY: 312 AN XY: 123818

Gnomad AFR exome AF: 0.0464

Gnomad AMR exome AF: 0.00301

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000764

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.00222

GnomAD4 exome AF: 0.00125 AC: 1777 AN: 1419298 Hom.: 38 Cov.: 32 AF XY: 0.00105 AC XY: 739 AN XY: 700620

Gnomad4 AFR exome AF: 0.0446

Gnomad4 AMR exome AF: 0.00287

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000488

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000544

Gnomad4 OTH exome AF: 0.00280

GnomAD4 genome AF: 0.0129 AC: 1955 AN: 151876 Hom.: 31 Cov.: 31 AF XY: 0.0125 AC XY: 928 AN XY: 74252

Gnomad4 AFR AF: 0.0443

Gnomad4 AMR AF: 0.00505

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.00706 Hom.: 7

Bravo AF: 0.0144

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 13, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.9
DANN	Benign	0.47

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: rs114809409; hg19: chr19-51955840;