Genetic Variant SIGLEC15:p.Arg122Gly (chr18-45837764-C-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_213602.3(SIGLEC15):c.364C>G(p.Arg122Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000073 in 1,369,270 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. R122C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.3e-7 ( 0 hom. )

Consequence

SIGLEC15
NM_213602.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.02

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2970357).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIGLEC15	NM_213602.3 link	c.364C>G	p.Arg122Gly	missense_variant	Exon 3 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.364C>G	p.Arg122Gly	missense_variant	Exon 3 of 6	1	NM_213602.3	ENSP00000374125.2		Q6ZMC9-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.30e-7

AC:

AN:

1369270

Hom.:

Cov.:

AF XY:

0.00000148

AC XY:

AN XY:

676892

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28154

American (AMR)

AF:

0.00

AC:

AN:

36246

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24266

East Asian (EAS)

AF:

0.00

AC:

AN:

32348

South Asian (SAS)

AF:

0.00

AC:

AN:

78176

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33702

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4202

European-Non Finnish (NFE)

AF:

9.30e-7

AC:

AN:

1075214

Other (OTH)

AF:

0.00

AC:

AN:

56962

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

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

0.16

BayesDel_addAF

Benign

-0.096

BayesDel_noAF

Benign

-0.38

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.045

Eigen

Benign

0.16

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.76

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.30

MetaSVM

Benign

-0.86

MutationAssessor

Benign

1.3

PhyloP100

5.0

PrimateAI

Pathogenic

0.81

PROVEAN

Uncertain

-3.5

REVEL

Benign

0.19

Sift

Uncertain

0.029

Sift4G

Benign

0.062

Polyphen

0.92

Vest4

0.20

MutPred

0.43

Loss of MoRF binding (P = 0.0149);

MVP

0.53

MPC

0.97

ClinPred

0.92

GERP RS

2.8

PromoterAI

-0.0069

Neutral

(source)

Varity_R

0.42

gMVP

0.44

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over