Variant 18-45837639-T-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.239T>C(p.Ile80Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00147 in 1,507,300 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00057 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0016 ( 0 hom. )

Consequence

SIGLEC15
NM_213602.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.92

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=0.21796441).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SIGLEC15	NM_213602.3 linkuse as main transcript	c.239T>C	p.Ile80Thr	missense_variant	3/6	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.239T>C	p.Ile80Thr	missense_variant	3/6	1	NM_213602.3	ENSP00000374125	P1	Q6ZMC9-1

Frequencies

GnomAD3 genomes

AF:

0.000572

AC:

AN:

152092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000378

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00102

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000458

AC:

AN:

102532

Hom.:

AF XY:

0.000561

AC XY:

AN XY:

57088

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000473

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00119

Gnomad OTH exome

AF:

0.000315

GnomAD4 exome

AF:

0.00157

AC:

2122

AN:

1355100

Hom.:

Cov.:

AF XY:

0.00154

AC XY:

1031

AN XY:

668308

show subpopulations

Gnomad4 AFR exome

AF:

0.000180

Gnomad4 AMR exome

AF:

0.0000608

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000150

Gnomad4 NFE exome

AF:

0.00193

Gnomad4 OTH exome

AF:

0.000796

GnomAD4 genome

AF:

0.000572

AC:

AN:

152200

Hom.:

Cov.:

AF XY:

0.000524

AC XY:

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.000265

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000378

Gnomad4 NFE

AF:

0.00102

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00106

Hom.:

Bravo

AF:

0.000548

ExAC

AF:

0.0000760

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

Jul 20, 2021

The c.239T>C (p.I80T) alteration is located in exon 3 (coding exon 3) of the SIGLEC15 gene. This alteration results from a T to C substitution at nucleotide position 239, causing the isoleucine (I) at amino acid position 80 to be replaced by a threonine (T). 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

Pathogenic

0.73

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.27

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.020

Eigen

Uncertain

0.19

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.69

M_CAP

Pathogenic

0.61

MetaRNN

Benign

0.22

MetaSVM

Benign

-0.77

MutationAssessor

Benign

1.8

MutationTaster

Benign

0.94

D;D

PrimateAI

Pathogenic

0.96

PROVEAN

Benign

-2.1

REVEL

Benign

0.28

Sift

Benign

0.039

Sift4G

Pathogenic

0.0

Polyphen

0.96

Vest4

0.30

MVP

0.61

MPC

0.71

ClinPred

0.094

GERP RS

3.5

Varity_R

0.20

gMVP

0.58

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