19-51455511-C-G

Variant names:

• chr19-51455511-C-G
• rs373970607
• NM_014442.3:c.958G>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.958G>C​(p.Val320Leu) 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. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V320M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SIGLEC8 NM_014442.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -5.10
• 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: 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=0.15325215).

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.958G>C	p.Val320Leu	missense	Exon 4 of 7	NP_055257.2	Q9NYZ4-1
	SIGLEC8	NM_001363548.1		c.679G>C	p.Val227Leu	missense	Exon 3 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.958G>C	p.Val320Leu	missense	Exon 4 of 7	ENSP00000321077.2	Q9NYZ4-1
	SIGLEC8	ENST00000340550.5	TSL:1	c.679G>C	p.Val227Leu	missense	Exon 3 of 6	ENSP00000339448.4	Q9NYZ4-2
	SIGLEC8	ENST00000853029.1		c.925G>C	p.Val309Leu	missense	Exon 4 of 7	ENSP00000523088.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251236 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.0030
DANN	Benign	0.23
DEOGEN2	Benign	0.00073	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.00085	N
LIST_S2	Benign	0.071	T
M_CAP	Benign	0.00066	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.37	N
PhyloP100		-5.1
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.17	N
REVEL	Benign	0.070
Sift	Benign	0.35	T
Sift4G	Benign	0.80	T
Polyphen		0.0070	B
Vest4		0.10
MutPred		0.74		Gain of sheet (P = 0.1945)
MVP		0.072
MPC		0.075
ClinPred		0.080	T
GERP RS		-4.4
Varity_R		0.034
gMVP		0.11
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: rs373970607; hg19: chr19-51958765;