chr18-45837585-T-G
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Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_213602.3(SIGLEC15):āc.185T>Gā(p.Leu62Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000264 in 1,512,468 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ).
Frequency
Genomes: š 0.00014 ( 0 hom., cov: 33)
Exomes š: 0.000014 ( 0 hom. )
Consequence
SIGLEC15
NM_213602.3 missense
NM_213602.3 missense
Scores
9
7
3
Clinical Significance
Conservation
PhyloP100: 4.52
Genes affected
SIGLEC15 (HGNC:27596): (sialic acid binding Ig like lectin 15) Predicted to be involved in regulation of actin cytoskeleton organization; regulation of bone resorption; and regulation of osteoclast development. Predicted to be integral component of membrane. Predicted to be part of protein-containing complex. Predicted to be active in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]
EPG5 (HGNC:29331): (ectopic P-granules 5 autophagy tethering factor) This gene encodes a large coiled coil domain-containing protein that functions in autophagy during starvation conditions. Mutations in this gene cause Vici syndrome. [provided by RefSeq, Aug 2015]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.965
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SIGLEC15 | NM_213602.3 | c.185T>G | p.Leu62Arg | missense_variant | 3/6 | ENST00000389474.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SIGLEC15 | ENST00000389474.8 | c.185T>G | p.Leu62Arg | missense_variant | 3/6 | 1 | NM_213602.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000138 AC: 21AN: 152100Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000278 AC: 3AN: 108062Hom.: 0 AF XY: 0.0000333 AC XY: 2AN XY: 59980
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GnomAD4 exome AF: 0.0000140 AC: 19AN: 1360260Hom.: 0 Cov.: 31 AF XY: 0.0000104 AC XY: 7AN XY: 671064
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GnomAD4 genome AF: 0.000138 AC: 21AN: 152208Hom.: 0 Cov.: 33 AF XY: 0.000134 AC XY: 10AN XY: 74424
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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 | Jan 03, 2024 | The c.185T>G (p.L62R) alteration is located in exon 3 (coding exon 3) of the SIGLEC15 gene. This alteration results from a T to G substitution at nucleotide position 185, causing the leucine (L) at amino acid position 62 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
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Uncertain
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MutPred
Gain of disorder (P = 0.0349);
MVP
MPC
ClinPred
D
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