chr18-45837585-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_213602.3(SIGLEC15):ā€‹c.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

Scores

9
7
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.52
Variant links:
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
SIGLEC15NM_213602.3 linkuse as main transcriptc.185T>G p.Leu62Arg missense_variant 3/6 ENST00000389474.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SIGLEC15ENST00000389474.8 linkuse as main transcriptc.185T>G p.Leu62Arg missense_variant 3/61 NM_213602.3 P1Q6ZMC9-1

Frequencies

GnomAD3 genomes
AF:
0.000138
AC:
21
AN:
152100
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000314
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000458
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.0000278
AC:
3
AN:
108062
Hom.:
0
AF XY:
0.0000333
AC XY:
2
AN XY:
59980
show subpopulations
Gnomad AFR exome
AF:
0.000907
Gnomad AMR exome
AF:
0.0000452
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:
0.0000140
AC:
19
AN:
1360260
Hom.:
0
Cov.:
31
AF XY:
0.0000104
AC XY:
7
AN XY:
671064
show subpopulations
Gnomad4 AFR exome
AF:
0.000392
Gnomad4 AMR exome
AF:
0.0000594
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:
0.000106
GnomAD4 genome
AF:
0.000138
AC:
21
AN:
152208
Hom.:
0
Cov.:
33
AF XY:
0.000134
AC XY:
10
AN XY:
74424
show subpopulations
Gnomad4 AFR
AF:
0.000313
Gnomad4 AMR
AF:
0.000457
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.000142
Hom.:
0
Bravo
AF:
0.000193

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 submitterclinical testingAmbry GeneticsJan 03, 2024The 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.96
BayesDel_addAF
Uncertain
0.11
D
BayesDel_noAF
Pathogenic
0.33
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Benign
0.35
T
Eigen
Uncertain
0.54
Eigen_PC
Uncertain
0.45
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Benign
0.75
T
M_CAP
Pathogenic
0.80
D
MetaRNN
Pathogenic
0.97
D
MetaSVM
Uncertain
0.37
D
MutationAssessor
Pathogenic
2.9
M
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.90
D
PROVEAN
Pathogenic
-4.5
D
REVEL
Pathogenic
0.90
Sift
Uncertain
0.0030
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.94
MutPred
0.87
Gain of disorder (P = 0.0349);
MVP
0.67
MPC
1.7
ClinPred
0.81
D
GERP RS
3.7
Varity_R
0.91
gMVP
0.95

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs528604727; hg19: chr18-43417550; API