18-45837783-G-C

Variant names:

• chr18-45837783-G-C
• rs777059196
• NM_213602.3:c.383G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_213602.3(SIGLEC15):​c.383G>C​(p.Arg128Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000459 in 1,523,654 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R128S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: SIGLEC15 NM_213602.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.84

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.848

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIGLEC15	NM_213602.3	c.383G>C	p.Arg128Pro	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.383G>C	p.Arg128Pro	missense_variant	Exon 3 of 6	1	NM_213602.3	ENSP00000374125.2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152186 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

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: 0.00000365 AC: 5 AN: 1371468 Hom.: 0 Cov.: 31 AF XY: 0.00000295 AC XY: 2 AN XY: 678088

African (AFR) AF: 0.000177 AC: 5 AN: 28208

American (AMR) AF: 0.00 AC: 0 AN: 36558

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 32592

South Asian (SAS) AF: 0.00 AC: 0 AN: 78500

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33712

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4334

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1076206

Other (OTH) AF: 0.00 AC: 0 AN: 57024

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152186 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74342

African (AFR) AF: 0.0000482 AC: 2 AN: 41468

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68010

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.383G>C (p.R128P) alteration is located in exon 3 (coding exon 3) of the SIGLEC15 gene. This alteration results from a G to C substitution at nucleotide position 383, causing the arginine (R) at amino acid position 128 to be replaced by a proline (P). 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	0.88
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.57	T
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Benign	-0.50	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		3.8
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.51
Sift	Benign	0.071	T
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.74
MutPred		0.62		Loss of MoRF binding (P = 0.0052);
MVP		0.63
MPC		1.6
ClinPred		0.97	D
GERP RS		3.7
PromoterAI		-0.071	Neutral
Varity_R		0.75
gMVP		0.89
Mutation Taster		=65/35	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: rs777059196; hg19: chr18-43417748;