chr18-45837558-G-C

Position:

• chr18-45837558-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_213602.3(SIGLEC15):​c.158G>C​(p.Ser53Thr) 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SIGLEC15 NM_213602.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.94

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

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=0.05159089).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIGLEC15	NM_213602.3	c.158G>C	p.Ser53Thr	missense_variant	3/6	ENST00000389474.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIGLEC15	ENST00000389474.8	c.158G>C	p.Ser53Thr	missense_variant	3/6	1	NM_213602.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 16, 2024

The c.158G>C (p.S53T) 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 158, causing the serine (S) at amino acid position 53 to be replaced by a threonine (T). 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	0.082
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	16
DANN	Benign	0.77
DEOGEN2	Benign	0.0017	T
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.052	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.69	N
MutationTaster	Benign	1.0	D;N
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	0.88	N
REVEL	Benign	0.043
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0050	B
Vest4		0.057
MutPred		0.34		Loss of disorder (P = 0.0761);
MVP		0.36
MPC		0.45
ClinPred		0.060	T
GERP RS		-0.25
Varity_R		0.048
gMVP		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: chr18-43417523;