rs766602179

Variant names:

• chr11-18296884-AG-A
• rs766602179
• NM_181507.2:c.1423delC

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_181507.2(HPS5):​c.1423delC​(p.Leu475SerfsTer37) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000297 in 1,613,578 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: HPS5 NM_181507.2 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7 U:1
• Conservation: PhyloP100: 0.968

Genes affected

HPS5 (HGNC:17022): (HPS5 biogenesis of lysosomal organelles complex 2 subunit 2) This gene encodes a protein that may play a role in organelle biogenesis associated with melanosomes, platelet dense granules, and lysosomes. This protein interacts with Hermansky-Pudlak syndrome 6 protein and may interact with the cytoplasmic domain of integrin, alpha-3. Mutations in this gene are associated with Hermansky-Pudlak syndrome type 5. Multiple transcript variants encoding two distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-18296884-AG-A is Pathogenic according to our data. Variant chr11-18296884-AG-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 431164.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=3, Likely_pathogenic=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPS5	NM_181507.2	c.1423delC	p.Leu475SerfsTer37	frameshift_variant	Exon 12 of 23	ENST00000349215.8	NP_852608.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HPS5	ENST00000349215.8	c.1423delC	p.Leu475SerfsTer37	frameshift_variant	Exon 12 of 23	1	NM_181507.2	ENSP00000265967.5
HPS5	ENST00000396253.7	c.1081delC	p.Leu361SerfsTer37	frameshift_variant	Exon 11 of 22	1		ENSP00000379552.3
HPS5	ENST00000438420.6	c.1081delC	p.Leu361SerfsTer37	frameshift_variant	Exon 11 of 22	1		ENSP00000399590.2
HPS5	ENST00000531848.1	c.1081delC	p.Leu361SerfsTer39	frameshift_variant	Exon 11 of 11	5		ENSP00000431758.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152020 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000795 AC: 20 AN: 251438 Hom.: 0 AF XY: 0.0000809 AC XY: 11 AN XY: 135890

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00169

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000308 AC: 45 AN: 1461558 Hom.: 0 Cov.: 31 AF XY: 0.0000261 AC XY: 19 AN XY: 727110

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00138

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152020 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74258

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000174 Hom.: 0

Bravo AF: 0.0000302

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hermansky-Pudlak syndrome 5 Pathogenic:3 Uncertain:1

May 06, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 02, 2017

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jun 13, 2019

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The HPS5 c.1423delC (p.Leu475SerfsTer37) variant results in a frameshift, and is predicted to result in premature termination of the protein. The p.Leu475SerfsTer37 variant has been reported in two studies in which it is found in two individuals with Hermansky-Pudlak syndrome including in one in a homozygous state and in one in a heterozygous state where a second variant was not detected (Carmona-Rivera et al. 2011; Ringeisen et al. 2013). Control data are unavailable for this variant, which is reported at a frequency of 0.00152 in the Ashkenazi Jewish population of the Genome Aggregation Database. Characterization of the heterozygous patient's fibroblasts revealed a complete absence of HPS5 protein (Carmona-Rivera et al. 2011). Based on the evidence and the potential impact of frameshift variants, the p.Leu475SerfsTer37 variant is classified as a variant of unknown significance, but suspicious for pathogenicity for Hermansky-Pudlak syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

not provided Pathogenic:2

Feb 21, 2018

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1423delC variant in the HPS5 gene has been reported previously in association with Hermansky-Pudlak syndrome, in an affected individual who was homozygous for the c.1423delC variant (reported as c.1081delC) and in an affected individual who was heterozygous for the c.1423delC variant, however no second HPS5 variant was identified (Ringeisen et al., 2013; Carmona-Rivera et al., 2011). The c.1423delC variant causes a frameshift starting with codon Leucine 475, changes this amino acid to a Serine residue, and creates a premature Stop codon at position 37 of the new reading frame, denoted p.Leu475SerfsX37. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.1423delC variant is observed in 18/246198 (0.007%) alleles in large population cohorts and no individuals were reported to be homozygous (Lek et al., 2016). We interpret c.1423delC as a likely pathogenic variant. -

Nov 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Leu475Serfs*37) in the HPS5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HPS5 are known to be pathogenic (PMID: 12548288, 15296495, 21833017, 26785811). This variant is present in population databases (rs766602179, gnomAD 0.2%). This premature translational stop signal has been observed in individual(s) with Hermansky-Pudlak syndrome (PMID: 21833017, 23607980). This variant is also known as 1081delC. ClinVar contains an entry for this variant (Variation ID: 431164). For these reasons, this variant has been classified as Pathogenic. -

Hermansky-Pudlak syndrome Pathogenic:2

Feb 28, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: HPS5 c.1423delC (p.Leu475SerfsX37) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been associated with Hermansky-Pudlak Syndrome in HGMD and classified as pathogenic in ClinVar. The variant allele was found at a frequency of 8e-05 in 251438 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in HPS5 causing Hermansky-Pudlak Syndrome (8e-05 vs 0.00047), allowing no conclusion about variant significance. c.1423delC has been reported in the literature in individuals affected with Hermansky-Pudlak Syndrome (Carmona-Rivera_2011, Ringeisen_2013). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified as VUS (n=1), Likely Pathogenic, (n=2) and Pathogenic(n=3). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Feb 01, 2019

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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

Other links and lift over

dbSNP: rs766602179; hg19: chr11-18318431;