19-51497412-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_053003.4(SIGLEC12):​c.1439G>A​(p.Gly480Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,460,922 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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)
Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

SIGLEC12
NM_053003.4 missense

Scores

2
1
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.79
Variant links:
Genes affected
SIGLEC12 (HGNC:15482): (sialic acid binding Ig like lectin 12) Sialic acid-binding immunoglobulin-like lectins (SIGLECs) are a family of cell surface proteins belonging to the immunoglobulin superfamily. They mediate protein-carbohydrate interactions by selectively binding to different sialic acid moieties present on glycolipids and glycoproteins. This gene encodes a member of the SIGLEC3-like subfamily of SIGLECs. Members of this subfamily are characterized by an extracellular V-set immunoglobulin-like domain followed by two C2-set immunoglobulin-like domains, and the cytoplasmic tyrosine-based motifs ITIM and SLAM-like. The encoded protein, upon tyrosine phosphorylation, has been shown to recruit the Src homology 2 domain-containing protein-tyrosine phosphatases SHP1 and SHP2. It has been suggested that the protein is involved in the negative regulation of macrophage signaling by functioning as an inhibitory receptor. This gene is located in a cluster with other SIGLEC3-like genes on 19q13.4. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.0895212).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SIGLEC12NM_053003.4 linkc.1439G>A p.Gly480Glu missense_variant Exon 6 of 8 ENST00000291707.8 NP_443729.1 Q96PQ1-1
SIGLEC12NM_033329.2 linkc.1085G>A p.Gly362Glu missense_variant Exon 5 of 7 NP_201586.1 Q96PQ1-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SIGLEC12ENST00000291707.8 linkc.1439G>A p.Gly480Glu missense_variant Exon 6 of 8 1 NM_053003.4 ENSP00000291707.3 Q96PQ1-1
SIGLEC12ENST00000596742.1 linkn.*654G>A non_coding_transcript_exon_variant Exon 6 of 8 1 ENSP00000469791.1 M0QYF3
SIGLEC12ENST00000596742.1 linkn.*654G>A 3_prime_UTR_variant Exon 6 of 8 1 ENSP00000469791.1 M0QYF3
SIGLEC12ENST00000598614.1 linkc.1085G>A p.Gly362Glu missense_variant Exon 5 of 7 5 ENSP00000472873.1 Q96PQ1-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000477
AC:
12
AN:
251372
Hom.:
0
AF XY:
0.0000368
AC XY:
5
AN XY:
135864
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000347
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000753
AC:
11
AN:
1460922
Hom.:
0
Cov.:
39
AF XY:
0.00000550
AC XY:
4
AN XY:
726788
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000246
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000756
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Oct 22, 2021
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1439G>A (p.G480E) alteration is located in exon 6 (coding exon 6) of the SIGLEC12 gene. This alteration results from a G to A substitution at nucleotide position 1439, causing the glycine (G) at amino acid position 480 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.21
BayesDel_addAF
Benign
-0.56
T
BayesDel_noAF
Benign
-0.73
CADD
Benign
0.11
DANN
Benign
0.50
DEOGEN2
Benign
0.023
T;.
Eigen
Benign
-1.2
Eigen_PC
Benign
-1.4
FATHMM_MKL
Benign
0.0057
N
LIST_S2
Benign
0.36
T;T
M_CAP
Benign
0.0012
T
MetaRNN
Benign
0.090
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Pathogenic
3.0
M;.
PrimateAI
Benign
0.34
T
PROVEAN
Pathogenic
-5.2
D;.
REVEL
Benign
0.037
Sift
Benign
0.036
D;.
Sift4G
Uncertain
0.058
T;D
Polyphen
0.014
B;P
Vest4
0.054
MutPred
0.61
Gain of sheet (P = 0.0344);.;
MVP
0.10
MPC
0.056
ClinPred
0.16
T
GERP RS
-1.1
Varity_R
0.16
gMVP
0.19

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs749781933; hg19: chr19-52000666; API