Genetic Variant NM_213602.3:c.418T>C (chr18-45837818-T-C) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_213602.3(SIGLEC15):c.418T>C(p.Tyr140His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000724 in 1,381,578 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: not found (cov: 33)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

SIGLEC15
NM_213602.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.33

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.969

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIGLEC15	NM_213602.3 link	c.418T>C	p.Tyr140His	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.418T>C	p.Tyr140His	missense_variant	Exon 3 of 6	1	NM_213602.3	ENSP00000374125.2		Q6ZMC9-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000150

AC:

AN:

133212

AF XY:

0.0000133

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000391

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000181

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.24e-7

AC:

AN:

1381578

Hom.:

Cov.:

AF XY:

0.00000146

AC XY:

AN XY:

683768

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28644

American (AMR)

AF:

0.0000268

AC:

AN:

37338

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24482

East Asian (EAS)

AF:

0.00

AC:

AN:

33254

South Asian (SAS)

AF:

0.00

AC:

AN:

79212

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34154

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4612

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1082344

Other (OTH)

AF:

0.00

AC:

AN:

57538

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

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 18, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.418T>C (p.Y140H) 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 418, causing the tyrosine (Y) at amino acid position 140 to be replaced by a histidine (H). 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

0.96

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.43

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.43

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.80

M_CAP

Pathogenic

0.40

MetaRNN

Pathogenic

0.97

MetaSVM

Pathogenic

0.98

MutationAssessor

Pathogenic

3.0

PhyloP100

7.3

PrimateAI

Pathogenic

0.91

PROVEAN

Pathogenic

-4.7

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.012

Polyphen

1.0

Vest4

0.95

MutPred

0.86

Gain of disorder (P = 0.0154);

MVP

0.88

MPC

1.6

ClinPred

0.97

GERP RS

4.0

PromoterAI

0.00050

Neutral

(source)

Varity_R

0.73

gMVP

0.89

Mutation Taster

=203/97

polymorphism

(source)

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

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over