NM_213602.3:c.11C>A

Variant names:

• chr18-45825739-C-A
• NM_213602.3:c.11C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_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. 16/22 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.371
• Publications: 0 publications found

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]

EPG5 Gene-Disease associations (from GenCC):

• Vici syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, G2P

ACMG classification

Our verdict: Likely_benign. The variant received -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 rank	MANE	Protein	UniProt
SIGLEC15	NM_213602.3	c.11C>A	p.Ser4Tyr	missense_variant	Exon 1 of 6	ENST00000389474.8	NP_998767.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIGLEC15	ENST00000389474.8	c.11C>A	p.Ser4Tyr	missense_variant	Exon 1 of 6	1	NM_213602.3	ENSP00000374125.2
EPG5	ENST00000696483.1	c.7558-24849G>T		intron_variant	Intron 43 of 43			ENSP00000512657.1
EPG5	ENST00000696484.1	c.7443-24849G>T		intron_variant	Intron 42 of 42			ENSP00000512658.1
EPG5	ENST00000696481.1	n.4075-24849G>T		intron_variant	Intron 15 of 15

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

Submissions by phenotype

not specified Uncertain:1

Jun 05, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The 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
PhyloP100		0.37
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
PromoterAI		0.025	Neutral
Varity_R		0.029
gMVP		0.42
Mutation Taster		=96/4	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

Other links and lift over

hg19: chr18-43405704;