19-51454696-A-G

Variant names:

• chr19-51454696-A-G
• NM_014442.3:c.1136T>C

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.1136T>C​(p.Ile379Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SIGLEC8 NM_014442.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.635
• 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=0.13443393).

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.1136T>C	p.Ile379Thr	missense	Exon 5 of 7	NP_055257.2	Q9NYZ4-1
	SIGLEC8	NM_001363548.1		c.857T>C	p.Ile286Thr	missense	Exon 4 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.1136T>C	p.Ile379Thr	missense	Exon 5 of 7	ENSP00000321077.2	Q9NYZ4-1
	SIGLEC8	ENST00000340550.5	TSL:1	c.857T>C	p.Ile286Thr	missense	Exon 4 of 6	ENSP00000339448.4	Q9NYZ4-2
	SIGLEC8	ENST00000853029.1		c.1103T>C	p.Ile368Thr	missense	Exon 5 of 7	ENSP00000523088.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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	Uncertain	0.36
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	15
DANN	Benign	0.94
DEOGEN2	Benign	0.027	T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.0094	N
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.7	L
PhyloP100		0.64
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.027
Sift	Uncertain	0.0050	D
Sift4G	Benign	0.10	T
Polyphen		0.87	P
Vest4		0.18
MutPred		0.48		Loss of stability (P = 0.0084)
MVP		0.46
MPC		0.12
ClinPred		0.35	T
GERP RS		2.3
Varity_R		0.12
gMVP		0.10
Mutation Taster		=96/4	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

hg19: chr19-51957950;