19-51458003-C-G
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong
The NM_014442.3(SIGLEC8):c.385G>C(p.Gly129Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00184 in 1,614,162 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.00076 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0020 ( 7 hom. )
Consequence
SIGLEC8
NM_014442.3 missense
NM_014442.3 missense
Scores
2
2
13
Clinical Significance
Conservation
PhyloP100: 0.743
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -4 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.024586916).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SIGLEC8 | NM_014442.3 | c.385G>C | p.Gly129Arg | missense_variant | 1/7 | ENST00000321424.7 | |
SIGLEC8 | NM_001363548.1 | c.385G>C | p.Gly129Arg | missense_variant | 1/6 | ||
SIGLEC8 | XM_011526734.3 | c.385G>C | p.Gly129Arg | missense_variant | 1/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SIGLEC8 | ENST00000321424.7 | c.385G>C | p.Gly129Arg | missense_variant | 1/7 | 1 | NM_014442.3 | P1 | |
SIGLEC8 | ENST00000340550.5 | c.385G>C | p.Gly129Arg | missense_variant | 1/6 | 1 | |||
SIGLEC8 | ENST00000430817.5 | c.385G>C | p.Gly129Arg | missense_variant | 1/6 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.000762 AC: 116AN: 152154Hom.: 0 Cov.: 32
GnomAD3 genomes
?
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GnomAD3 exomes AF: 0.000688 AC: 173AN: 251484Hom.: 0 AF XY: 0.000736 AC XY: 100AN XY: 135914
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GnomAD4 exome AF: 0.00196 AC: 2862AN: 1461890Hom.: 7 Cov.: 32 AF XY: 0.00196 AC XY: 1422AN XY: 727248
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GnomAD4 genome ? AF: 0.000755 AC: 115AN: 152272Hom.: 0 Cov.: 32 AF XY: 0.000578 AC XY: 43AN XY: 74444
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 09, 2021 | The c.385G>C (p.G129R) alteration is located in exon 1 (coding exon 1) of the SIGLEC8 gene. This alteration results from a G to C substitution at nucleotide position 385, causing the glycine (G) at amino acid position 129 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Uncertain
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T;T;T
M_CAP
Benign
T
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
N;N;N
PrimateAI
Benign
T
PROVEAN
Pathogenic
D;D;D
REVEL
Benign
Sift
Benign
D;D;T
Sift4G
Uncertain
D;D;D
Polyphen
D;D;D
Vest4
MutPred
Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);
MVP
MPC
0.37
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at