19-51451604-T-C

Variant names:

• chr19-51451604-T-C
• rs39711
• NM_014442.3:c.*775A>G

Variant summary

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

The NM_014442.3(SIGLEC8):​c.*775A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.345 in 152,080 control chromosomes in the GnomAD database, including 10,449 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 0.34 (10449 hom., cov: 32)
  • Exomes 𝑓: 0.50 (3 hom.)
  • Failed GnomAD Quality Control
• Consequence: SIGLEC8 NM_014442.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.575
• Publications: 5 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=-0.95).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.538 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIGLEC8	NM_014442.3	MANE Select	c.*775A>G		3_prime_UTR	Exon 7 of 7	NP_055257.2
	SIGLEC8	NM_001363548.1		c.*775A>G		3_prime_UTR	Exon 6 of 6	NP_001350477.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIGLEC8	ENST00000321424.7	TSL:1 MANE Select	c.*775A>G		3_prime_UTR	Exon 7 of 7	ENSP00000321077.2
	SIGLEC8	ENST00000430817.5	TSL:2	c.*42-509A>G		intron	N/A	ENSP00000389142.1

Frequencies

GnomAD3 genomes AF: 0.344 AC: 52347 AN: 151962 Hom.: 10419 Cov.: 32

Gnomad AFR AF: 0.528

Gnomad AMI AF: 0.264

Gnomad AMR AF: 0.253

Gnomad ASJ AF: 0.192

Gnomad EAS AF: 0.554

Gnomad SAS AF: 0.294

Gnomad FIN AF: 0.335

Gnomad MID AF: 0.291

Gnomad NFE AF: 0.253

Gnomad OTH AF: 0.319

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.500 AC: 14 AN: 28 Hom.: 3 Cov.: 0 AF XY: 0.611 AC XY: 11 AN XY: 18

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

African (AFR) AF: 0.750 AC: 3 AN: 4

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.500 AC: 1 AN: 2

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.556 AC: 10 AN: 18

Other (OTH) AC: 0 AN: 0

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0102767), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.345 AC: 52425 AN: 152080 Hom.: 10449 Cov.: 32 AF XY: 0.347 AC XY: 25810 AN XY: 74342

African (AFR) AF: 0.528 AC: 21908 AN: 41456

American (AMR) AF: 0.252 AC: 3854 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.192 AC: 666 AN: 3468

East Asian (EAS) AF: 0.555 AC: 2863 AN: 5160

South Asian (SAS) AF: 0.294 AC: 1419 AN: 4820

European-Finnish (FIN) AF: 0.335 AC: 3549 AN: 10584

Middle Eastern (MID) AF: 0.279 AC: 82 AN: 294

European-Non Finnish (NFE) AF: 0.252 AC: 17164 AN: 67984

Other (OTH) AF: 0.322 AC: 680 AN: 2112

Alfa AF: 0.278 Hom.: 28616

Bravo AF: 0.345

Asia WGS AF: 0.445 AC: 1550 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	2.6
DANN	Benign	0.77
PhyloP100		-0.57
Mutation Taster		=99/1	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: rs39711; hg19: chr19-51954858;