NM_014442.3:c.1293T>A

Variant names:

• chr19-51452586-A-T
• rs114809409
• NM_014442.3:c.1293T>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_014442.3(SIGLEC8):​c.1293T>A​(p.Pro431Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000705 in 1,419,300 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. P431P) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: SIGLEC8 NM_014442.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.43
• 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.04).
• BP7: Synonymous conserved (PhyloP=-3.43 with no splicing effect.

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.1293T>A	p.Pro431Pro	synonymous	Exon 7 of 7	NP_055257.2	Q9NYZ4-1
	SIGLEC8	NM_001363548.1		c.1014T>A	p.Pro338Pro	synonymous	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.1293T>A	p.Pro431Pro	synonymous	Exon 7 of 7	ENSP00000321077.2	Q9NYZ4-1
	SIGLEC8	ENST00000340550.5	TSL:1	c.1014T>A	p.Pro338Pro	synonymous	Exon 6 of 6	ENSP00000339448.4	Q9NYZ4-2
	SIGLEC8	ENST00000853029.1		c.1260T>A	p.Pro420Pro	synonymous	Exon 7 of 7	ENSP00000523088.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.05e-7 AC: 1 AN: 1419300 Hom.: 0 Cov.: 32 AF XY: 0.00000143 AC XY: 1 AN XY: 700622

African (AFR) AF: 0.00 AC: 0 AN: 31934

American (AMR) AF: 0.00 AC: 0 AN: 40410

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24522

East Asian (EAS) AF: 0.00 AC: 0 AN: 38912

South Asian (SAS) AF: 0.00 AC: 0 AN: 81988

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52354

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5530

European-Non Finnish (NFE) AF: 9.21e-7 AC: 1 AN: 1085380

Other (OTH) AF: 0.00 AC: 0 AN: 58270

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.8
DANN	Benign	0.40
PhyloP100		-3.4

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: rs114809409; hg19: chr19-51955840;