rs766602179

Positions:

chr11-18296884-AG-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_181507.2(HPS5):c.1423del(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

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U:1

Conservation

PhyloP100: 0.968

Variant links:

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]

HPS5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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: {Pathogenic=2, Uncertain_significance=1, Likely_pathogenic=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HPS5	NM_181507.2 linkuse as main transcript	c.1423del	p.Leu475SerfsTer37	frameshift_variant	12/23	ENST00000349215.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HPS5	ENST00000349215.8 linkuse as main transcript	c.1423del	p.Leu475SerfsTer37	frameshift_variant	12/23	1	NM_181507.2	P1	Q9UPZ3-1
HPS5	ENST00000396253.7 linkuse as main transcript	c.1081del	p.Leu361SerfsTer37	frameshift_variant	11/22	1			Q9UPZ3-2
HPS5	ENST00000438420.6 linkuse as main transcript	c.1081del	p.Leu361SerfsTer37	frameshift_variant	11/22	1			Q9UPZ3-2
HPS5	ENST00000531848.1 linkuse as main transcript	c.1081del	p.Leu361SerfsTer39	frameshift_variant	11/11	5

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152020

Hom.:

Cov.:

show subpopulations

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:

AN:

251438

Hom.:

AF XY:

0.0000809

AC XY:

AN XY:

135890

show subpopulations

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:

AN:

1461558

Hom.:

Cov.:

AF XY:

0.0000261

AC XY:

AN XY:

727110

show subpopulations

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:

AN:

152020

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74258

show subpopulations

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.:

Bravo

AF:

0.0000302

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hermansky-Pudlak syndrome 5

Pathogenic:2Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 02, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 13, 2019	- -

Hermansky-Pudlak syndrome

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 28, 2023	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. -
Likely pathogenic, criteria provided, single submitter	research	NIHR Bioresource Rare Diseases, University of Cambridge	Feb 01, 2019	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 19, 2023	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 21, 2018	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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

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