18-45837782-C-A

Variant names:

• chr18-45837782-C-A
• rs1303956994
• NM_213602.3:c.382C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_213602.3(SIGLEC15):​c.382C>A​(p.Arg128Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000125 in 1,523,654 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R128P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: SIGLEC15 NM_213602.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.51

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36389077).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIGLEC15	NM_213602.3	c.382C>A	p.Arg128Ser	missense_variant	Exon 3 of 6	ENST00000389474.8	NP_998767.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIGLEC15	ENST00000389474.8	c.382C>A	p.Arg128Ser	missense_variant	Exon 3 of 6	1	NM_213602.3	ENSP00000374125.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152192 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

GnomAD4 exome AF: 0.0000131 AC: 18 AN: 1371462 Hom.: 0 Cov.: 31 AF XY: 0.0000103 AC XY: 7 AN XY: 678120

African (AFR) AF: 0.0000354 AC: 1 AN: 28216

American (AMR) AF: 0.00 AC: 0 AN: 36510

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24334

East Asian (EAS) AF: 0.00 AC: 0 AN: 32612

South Asian (SAS) AF: 0.00 AC: 0 AN: 78456

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33704

Middle Eastern (MID) AF: 0.000459 AC: 2 AN: 4354

European-Non Finnish (NFE) AF: 0.0000139 AC: 15 AN: 1076234

Other (OTH) AF: 0.00 AC: 0 AN: 57042

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152192 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74338

African (AFR) AF: 0.0000241 AC: 1 AN: 41460

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 11, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.382C>A (p.R128S) alteration is located in exon 3 (coding exon 3) of the SIGLEC15 gene. This alteration results from a C to A substitution at nucleotide position 382, causing the arginine (R) at amino acid position 128 to be replaced by a serine (S). 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	Uncertain	0.46
BayesDel_addAF	Uncertain	0.046	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0034	T
Eigen	Benign	0.023
Eigen_PC	Benign	0.070
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.56	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.39	N
PhyloP100		2.5
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.81	N
REVEL	Benign	0.27
Sift	Benign	0.59	T
Sift4G	Uncertain	0.0090	D
Polyphen		0.92	P
Vest4		0.36
MutPred		0.60		Loss of MoRF binding (P = 0.0191);
MVP		0.60
MPC		1.1
ClinPred		0.83	D
GERP RS		2.8
PromoterAI		0.013	Neutral
Varity_R		0.32
gMVP		0.70
Mutation Taster		=76/24	polymorphism

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

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Other links and lift over

dbSNP: rs1303956994; hg19: chr18-43417747;