18-45825739-C-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_213602.3(SIGLEC15):​c.11C>A​(p.Ser4Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 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)

Consequence

SIGLEC15
NM_213602.3 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.371
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_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.06321356).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SIGLEC15NM_213602.3 linkuse as main transcriptc.11C>A p.Ser4Tyr missense_variant 1/6 ENST00000389474.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SIGLEC15ENST00000389474.8 linkuse as main transcriptc.11C>A p.Ser4Tyr missense_variant 1/61 NM_213602.3 P1Q6ZMC9-1
EPG5ENST00000696483.1 linkuse as main transcriptc.7558-24849G>T intron_variant
EPG5ENST00000696484.1 linkuse as main transcriptc.7443-24849G>T intron_variant
EPG5ENST00000696481.1 linkuse as main transcriptn.4075-24849G>T intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

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 GeneticsJun 05, 2024The c.11C>A (p.S4Y) alteration is located in exon 1 (coding exon 1) of the SIGLEC15 gene. This alteration results from a C to A substitution at nucleotide position 11, causing the serine (S) at amino acid position 4 to be replaced by a tyrosine (Y). 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
0.10
BayesDel_addAF
Benign
-0.28
T
BayesDel_noAF
Benign
-0.65
CADD
Benign
11
DANN
Benign
0.85
DEOGEN2
Benign
0.0019
T
Eigen
Benign
-1.1
Eigen_PC
Benign
-1.1
FATHMM_MKL
Benign
0.11
N
LIST_S2
Benign
0.41
T
M_CAP
Benign
0.0093
T
MetaRNN
Benign
0.063
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.55
N
MutationTaster
Benign
1.0
N
PrimateAI
Benign
0.34
T
PROVEAN
Benign
-0.40
N
REVEL
Benign
0.010
Sift
Benign
0.33
T
Sift4G
Pathogenic
0.0
D
Polyphen
0.28
B
Vest4
0.13
MutPred
0.30
Loss of disorder (P = 0.0199);
MVP
0.10
MPC
0.68
ClinPred
0.080
T
GERP RS
0.94
Varity_R
0.029
gMVP
0.42

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr18-43405704; API