rs281865101

Variant names:

• chr11-18305438-T-TG
• rs281865101
• NM_181507.2:c.879dupC

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_181507.2(HPS5):​c.879dupC​(p.Lys294GlnfsTer6) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,455,752 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: HPS5 NM_181507.2 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 0.741

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

Our verdict: Pathogenic. The variant received 12 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 11-18305438-T-TG is Pathogenic according to our data. Variant chr11-18305438-T-TG is described in ClinVar as [Pathogenic]. Clinvar id is 21822.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPS5	NM_181507.2	c.879dupC	p.Lys294GlnfsTer6	frameshift_variant	Exon 8 of 23	ENST00000349215.8	NP_852608.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HPS5	ENST00000349215.8	c.879dupC	p.Lys294GlnfsTer6	frameshift_variant	Exon 8 of 23	1	NM_181507.2	ENSP00000265967.5
HPS5	ENST00000396253.7	c.537dupC	p.Lys180GlnfsTer6	frameshift_variant	Exon 7 of 22	1		ENSP00000379552.3
HPS5	ENST00000438420.6	c.537dupC	p.Lys180GlnfsTer6	frameshift_variant	Exon 7 of 22	1		ENSP00000399590.2
HPS5	ENST00000531848.1	c.537dupC	p.Lys180GlnfsTer6	frameshift_variant	Exon 7 of 11	5		ENSP00000431758.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1455752 Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1 AN XY: 724652

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33334

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44702

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26086

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39606

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 86094

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53332

Gnomad4 NFE exome AF: 0.00000271 AC: 3 AN: 1106686

Gnomad4 Remaining exome AF: 0.00 AC: 0 AN: 60158

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Hermansky-Pudlak syndrome 5 Pathogenic:1

Sep 01, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Mar 20, 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.Lys294Glnfs*6) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Hermansky–Pudlak syndrome (PMID: 15296495). This variant is also known as P293insC. ClinVar contains an entry for this variant (Variation ID: 21822). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mutation Taster		=0/200	disease causing (ClinVar)

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

LitVar

Other links and lift over

dbSNP: rs281865101; hg19: chr11-18326985;