Variant 18-45837069-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_213602.3(SIGLEC15):c.93G>C(p.Leu31Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,448,956 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SIGLEC15
NM_213602.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.154

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]

SIGLEC15 links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0897831).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SIGLEC15	NM_213602.3 linkuse as main transcript	c.93G>C	p.Leu31Phe	missense_variant	2/6	ENST00000389474.8	NP_998767.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SIGLEC15	ENST00000389474.8 linkuse as main transcript	c.93G>C	p.Leu31Phe	missense_variant	2/6	1	NM_213602.3	ENSP00000374125	P1	Q6ZMC9-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1448956

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

721740

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000182

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

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 submitter

clinical testing

Ambry Genetics

Sep 01, 2021

The c.93G>C (p.L31F) alteration is located in exon 2 (coding exon 2) of the SIGLEC15 gene. This alteration results from a G to C substitution at nucleotide position 93, causing the leucine (L) at amino acid position 31 to be replaced by a phenylalanine (F). 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

0.080

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.63

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Benign

0.011

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.032

LIST_S2

Benign

0.46

M_CAP

Benign

0.0045

MetaRNN

Benign

0.090

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.39

PROVEAN

Benign

-1.7

REVEL

Benign

0.060

Sift

Uncertain

0.016

Sift4G

Pathogenic

0.0

Polyphen

0.74

Vest4

0.16

MutPred

0.40

Gain of catalytic residue at L31 (P = 0.0556);

MVP

0.12

MPC

0.80

ClinPred

0.15

GERP RS

-2.4

Varity_R

0.091

gMVP

0.40

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over