chr19-51452585-G-A

Variant names:

• chr19-51452585-G-A
• rs1989391138
• NM_014442.3:c.1294C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014442.3(SIGLEC8):​c.1294C>T​(p.Pro432Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000702 in 1,423,788 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: SIGLEC8 NM_014442.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0770
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12461874).

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.1294C>T	p.Pro432Ser	missense	Exon 7 of 7	NP_055257.2	Q9NYZ4-1
	SIGLEC8	NM_001363548.1		c.1015C>T	p.Pro339Ser	missense	Exon 6 of 6	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.1294C>T	p.Pro432Ser	missense	Exon 7 of 7	ENSP00000321077.2	Q9NYZ4-1
	SIGLEC8	ENST00000340550.5	TSL:1	c.1015C>T	p.Pro339Ser	missense	Exon 6 of 6	ENSP00000339448.4	Q9NYZ4-2
	SIGLEC8	ENST00000853029.1		c.1261C>T	p.Pro421Ser	missense	Exon 7 of 7	ENSP00000523088.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.02e-7 AC: 1 AN: 1423788 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 703080

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

African (AFR) AF: 0.00 AC: 0 AN: 32082

American (AMR) AF: 0.0000244 AC: 1 AN: 40984

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24820

East Asian (EAS) AF: 0.00 AC: 0 AN: 38950

South Asian (SAS) AF: 0.00 AC: 0 AN: 82804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52568

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5568

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1087538

Other (OTH) AF: 0.00 AC: 0 AN: 58474

⚠️ 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 Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	4.1
DANN	Benign	0.87
DEOGEN2	Benign	0.0053	T
Eigen	Benign	-0.93
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0049	N
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.077
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.024
Sift	Benign	0.26	T
Sift4G	Benign	0.32	T
Polyphen		0.47	P
Vest4		0.17
MutPred		0.48		Loss of catalytic residue at P432 (P = 0.0091)
MVP		0.52
MPC		0.20
ClinPred		0.17	T
GERP RS		-1.5
Varity_R		0.043
gMVP		0.058
Mutation Taster		=100/0	polymorphism

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: rs1989391138; hg19: chr19-51955839; COSMIC: COSV58473907; COSMIC: COSV58473907;