18-45837733-C-T

Variant names:

• chr18-45837733-C-T
• rs777583258
• NM_213602.3:c.333C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The NM_213602.3(SIGLEC15):​c.333C>T​(p.His111His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000222 in 1,354,136 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.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: SIGLEC15 NM_213602.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.329
• Publications: 0 publications found

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]

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

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP7: Synonymous conserved (PhyloP=0.329 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIGLEC15	NM_213602.3	c.333C>T	p.His111His	synonymous_variant	Exon 3 of 6	ENST00000389474.8	NP_998767.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIGLEC15	ENST00000389474.8	c.333C>T	p.His111His	synonymous_variant	Exon 3 of 6	1	NM_213602.3	ENSP00000374125.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000222 AC: 3 AN: 1354136 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 668344

African (AFR) AF: 0.00 AC: 0 AN: 27578

American (AMR) AF: 0.00 AC: 0 AN: 33372

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23864

East Asian (EAS) AF: 0.00 AC: 0 AN: 31324

South Asian (SAS) AF: 0.00 AC: 0 AN: 76322

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33354

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4060

European-Non Finnish (NFE) AF: 0.00000281 AC: 3 AN: 1067884

Other (OTH) AF: 0.00 AC: 0 AN: 56378

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	12
DANN	Benign	0.97
PhyloP100		0.33
PromoterAI		-0.056	Neutral

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

Other links and lift over

dbSNP: rs777583258; hg19: chr18-43417698;