Variant 18-45837733-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_213602.3(SIGLEC15):c.333C>G(p.His111Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000643 in 1,506,386 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00051 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00066 ( 0 hom. )

Consequence

SIGLEC15
NM_213602.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.329

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:

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ACMG classification

Classification made for transcript

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=0.00605458).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIGLEC15	NM_213602.3 linkuse as main transcript	c.333C>G	p.His111Gln	missense_variant	3/6	ENST00000389474.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIGLEC15	ENST00000389474.8 linkuse as main transcript	c.333C>G	p.His111Gln	missense_variant	3/6	1	NM_213602.3	P1	Q6ZMC9-1

Frequencies

GnomAD3 genomes

AF:

0.000513

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00292

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000574

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000456

AC:

AN:

103182

Hom.:

AF XY:

0.000429

AC XY:

AN XY:

58322

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000139

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000359

Gnomad FIN exome

AF:

0.00266

Gnomad NFE exome

AF:

0.000565

Gnomad OTH exome

AF:

0.000332

GnomAD4 exome

AF:

0.000657

AC:

890

AN:

1354136

Hom.:

Cov.:

AF XY:

0.000619

AC XY:

414

AN XY:

668346

show subpopulations

Gnomad4 AFR exome

AF:

0.0000725

Gnomad4 AMR exome

AF:

0.0000899

Gnomad4 ASJ exome

AF:

0.0000419

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000380

Gnomad4 FIN exome

AF:

0.00234

Gnomad4 NFE exome

AF:

0.000704

Gnomad4 OTH exome

AF:

0.000443

GnomAD4 genome

AF:

0.000512

AC:

AN:

152250

Hom.:

Cov.:

AF XY:

0.000658

AC XY:

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00292

Gnomad4 NFE

AF:

0.000574

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000997

Hom.:

Bravo

AF:

0.000325

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000778

AC:

ExAC

AF:

0.000171

AC:

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 06, 2022

The c.333C>G (p.H111Q) alteration is located in exon 3 (coding exon 3) of the SIGLEC15 gene. This alteration results from a C to G substitution at nucleotide position 333, causing the histidine (H) at amino acid position 111 to be replaced by a glutamine (Q). 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

0.11

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Benign

0.86

DEOGEN2

Benign

0.0017

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.50

FATHMM_MKL

Benign

0.62

LIST_S2

Benign

0.32

MetaRNN

Benign

0.0061

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-0.61

MutationTaster

Benign

1.0

D;N

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

0.25

REVEL

Benign

0.061

Sift

Benign

0.84

Sift4G

Benign

0.22

Polyphen

0.52

Vest4

0.077

MutPred

0.35

Gain of disorder (P = 0.045);

MVP

0.54

MPC

0.50

ClinPred

0.050

GERP RS

1.1

Varity_R

0.080

gMVP

0.37

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

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