Genetic Variant NM_213602.3:c.190T>G (chr18-45837590-T-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PP3_Strong

The NM_213602.3(SIGLEC15):c.190T>G(p.Cys64Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000245 in 1,512,830 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

SIGLEC15
NM_213602.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.61

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.99

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIGLEC15	NM_213602.3 link	c.190T>G	p.Cys64Gly	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.190T>G	p.Cys64Gly	missense_variant	Exon 3 of 6	1	NM_213602.3	ENSP00000374125.2		Q6ZMC9-1

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152070

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000189

AC:

AN:

105552

AF XY:

0.0000170

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000184

AC:

AN:

1360760

Hom.:

Cov.:

AF XY:

0.0000209

AC XY:

AN XY:

671378

show subpopulations

African (AFR)

AF:

0.000142

AC:

AN:

28094

American (AMR)

AF:

0.0000296

AC:

AN:

33802

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24308

East Asian (EAS)

AF:

0.00

AC:

AN:

33080

South Asian (SAS)

AF:

0.000220

AC:

AN:

77154

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33372

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4082

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1070126

Other (OTH)

AF:

0.0000529

AC:

AN:

56742

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000789

AC:

AN:

152070

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74288

show subpopulations

African (AFR)

AF:

0.000193

AC:

AN:

41424

American (AMR)

AF:

0.0000655

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.000621

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67986

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000604

ExAC

AF:

0.0000184

AC:

Asia WGS

AF:

0.000290

AC:

AN:

3462

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 12, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.190T>G (p.C64G) alteration is located in exon 3 (coding exon 3) of the SIGLEC15 gene. This alteration results from a T to G substitution at nucleotide position 190, causing the cysteine (C) at amino acid position 64 to be replaced by a glycine (G). 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

0.95

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Pathogenic

0.22

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.44

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.72

M_CAP

Pathogenic

0.80

MetaRNN

Pathogenic

0.99

MetaSVM

Uncertain

0.20

MutationAssessor

Pathogenic

3.1

PhyloP100

5.6

PrimateAI

Pathogenic

0.94

PROVEAN

Pathogenic

-10

REVEL

Pathogenic

0.77

Sift

Uncertain

0.0070

Sift4G

Pathogenic

0.0

Polyphen

0.99

Vest4

0.92

MutPred

0.96

Loss of catalytic residue at P63 (P = 0.0134);

MVP

0.65

MPC

1.5

ClinPred

1.0

GERP RS

3.7

PromoterAI

-0.0061

Neutral

(source)

Varity_R

0.92

gMVP

0.91

Mutation Taster

=207/93

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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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NM_213602.3:c.190T>G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over