Genetic Variant SIGLEC15:p.Glu29Gln (chr18-45837061-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_213602.3(SIGLEC15):c.85G>C(p.Glu29Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000701 in 1,426,066 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E29K) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

SIGLEC15
NM_213602.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.625

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

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

EPG5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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=0.055537164).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIGLEC15	NM_213602.3 link	c.85G>C	p.Glu29Gln	missense_variant	Exon 2 of 6	ENST00000389474.8	NP_998767.1	Q6ZMC9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIGLEC15	ENST00000389474.8 link	c.85G>C	p.Glu29Gln	missense_variant	Exon 2 of 6	1	NM_213602.3	ENSP00000374125.2		Q6ZMC9-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.01e-7

AC:

AN:

1426066

Hom.:

Cov.:

AF XY:

0.00000141

AC XY:

AN XY:

711648

show subpopulations

African (AFR)

AF:

0.0000306

AC:

AN:

32690

American (AMR)

AF:

0.00

AC:

AN:

44664

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25912

East Asian (EAS)

AF:

0.00

AC:

AN:

39556

South Asian (SAS)

AF:

0.00

AC:

AN:

85468

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53186

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5664

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1079760

Other (OTH)

AF:

0.00

AC:

AN:

59166

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.73

CADD

Benign

(source)

DANN

Benign

0.76

DEOGEN2

Benign

0.00041

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.051

LIST_S2

Benign

0.47

M_CAP

Benign

0.0028

MetaRNN

Benign

0.056

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

PhyloP100

0.63

PrimateAI

Benign

0.31

PROVEAN

Benign

0.020

REVEL

Benign

0.016

Sift

Benign

0.30

Sift4G

Benign

0.47

Polyphen

0.089

Vest4

0.078

MutPred

0.43

Loss of sheet (P = 0.0817);

MVP

0.30

MPC

0.47

ClinPred

0.062

GERP RS

2.5

Varity_R

0.066

gMVP

0.40

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.18

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

18-45837061-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over