19-51454423-C-T

Variant names:

• chr19-51454423-C-T
• rs10408249
• NM_014442.3:c.1149-108G>A

Variant summary

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

The NM_014442.3(SIGLEC8):​c.1149-108G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.262 in 1,589,100 control chromosomes in the GnomAD database, including 58,389 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 0.33 (9599 hom., cov: 31)
  • Exomes 𝑓: 0.25 (48790 hom.)
• Consequence: SIGLEC8 NM_014442.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.70
• Publications: 1 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=-0.98).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.519 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIGLEC8	NM_014442.3	c.1149-108G>A		intron_variant	Intron 5 of 6	ENST00000321424.7	NP_055257.2
SIGLEC8	NM_001363548.1	c.870-108G>A		intron_variant	Intron 4 of 5		NP_001350477.1
SIGLEC8	XM_011526734.3	c.1116-108G>A		intron_variant	Intron 5 of 6		XP_011525036.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIGLEC8	ENST00000321424.7	c.1149-108G>A		intron_variant	Intron 5 of 6	1	NM_014442.3	ENSP00000321077.2
SIGLEC8	ENST00000340550.5	c.870-108G>A		intron_variant	Intron 4 of 5	1		ENSP00000339448.4
SIGLEC8	ENST00000430817.5	c.822-108G>A		intron_variant	Intron 3 of 5	2		ENSP00000389142.1

Frequencies

GnomAD3 genomes AF: 0.331 AC: 50160 AN: 151756 Hom.: 9562 Cov.: 31

Gnomad AFR AF: 0.524

Gnomad AMI AF: 0.265

Gnomad AMR AF: 0.247

Gnomad ASJ AF: 0.193

Gnomad EAS AF: 0.221

Gnomad SAS AF: 0.244

Gnomad FIN AF: 0.349

Gnomad MID AF: 0.323

Gnomad NFE AF: 0.252

Gnomad OTH AF: 0.314

GnomAD4 exome AF: 0.255 AC: 366476 AN: 1437226 Hom.: 48790 AF XY: 0.253 AC XY: 180597 AN XY: 714892

African (AFR) AF: 0.536 AC: 17298 AN: 32248

American (AMR) AF: 0.211 AC: 8577 AN: 40724

Ashkenazi Jewish (ASJ) AF: 0.189 AC: 4822 AN: 25568

East Asian (EAS) AF: 0.268 AC: 10562 AN: 39342

South Asian (SAS) AF: 0.233 AC: 19729 AN: 84550

European-Finnish (FIN) AF: 0.342 AC: 17945 AN: 52530

Middle Eastern (MID) AF: 0.229 AC: 927 AN: 4050

European-Non Finnish (NFE) AF: 0.247 AC: 271183 AN: 1098930

Other (OTH) AF: 0.260 AC: 15433 AN: 59284

GnomAD4 genome AF: 0.331 AC: 50252 AN: 151874 Hom.: 9599 Cov.: 31 AF XY: 0.331 AC XY: 24555 AN XY: 74200

African (AFR) AF: 0.525 AC: 21724 AN: 41396

American (AMR) AF: 0.247 AC: 3765 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.193 AC: 669 AN: 3472

East Asian (EAS) AF: 0.222 AC: 1147 AN: 5168

South Asian (SAS) AF: 0.244 AC: 1178 AN: 4818

European-Finnish (FIN) AF: 0.349 AC: 3665 AN: 10516

Middle Eastern (MID) AF: 0.313 AC: 92 AN: 294

European-Non Finnish (NFE) AF: 0.252 AC: 17095 AN: 67932

Other (OTH) AF: 0.320 AC: 676 AN: 2110

Alfa AF: 0.273 Hom.: 8141

Bravo AF: 0.331

Asia WGS AF: 0.304 AC: 1060 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.40
DANN	Benign	0.45
PhyloP100		-4.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10408249; hg19: chr19-51957677; COSMIC: COSV58474497; COSMIC: COSV58474497;