rs397507169

Variant names:

• chr11-18285367-G-GTC
• rs397507169
• NM_181507.2:c.2928_2929dupGA

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_181507.2(HPS5):​c.2928_2929dupGA​(p.Thr977ArgfsTer15) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T977T) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HPS5 NM_181507.2 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: -0.0280
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• Hermansky-Pudlak syndrome 5

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen
• Hermansky-Pudlak syndrome without pulmonary fibrosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 18 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 11-18285367-G-GTC is Pathogenic according to our data. Variant chr11-18285367-G-GTC is described in ClinVar as Pathogenic. ClinVar VariationId is 21820.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181507.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPS5	NM_181507.2	MANE Select	c.2928_2929dupGA	p.Thr977ArgfsTer15	frameshift	Exon 20 of 23	NP_852608.1
	HPS5	NM_001440902.1		c.2928_2929dupGA	p.Thr977ArgfsTer15	frameshift	Exon 20 of 24	NP_001427831.1
	HPS5	NM_001440903.1		c.2928_2929dupGA	p.Thr977ArgfsTer15	frameshift	Exon 20 of 24	NP_001427832.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPS5	ENST00000349215.8	TSL:1 MANE Select	c.2928_2929dupGA	p.Thr977ArgfsTer15	frameshift	Exon 20 of 23	ENSP00000265967.5
	HPS5	ENST00000396253.7	TSL:1	c.2586_2587dupGA	p.Thr863ArgfsTer15	frameshift	Exon 19 of 22	ENSP00000379552.3
	HPS5	ENST00000438420.6	TSL:1	c.2586_2587dupGA	p.Thr863ArgfsTer15	frameshift	Exon 19 of 22	ENSP00000399590.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.86e-7 AC: 1 AN: 1458498 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 725780

African (AFR) AF: 0.00 AC: 0 AN: 33396

American (AMR) AF: 0.00 AC: 0 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39620

South Asian (SAS) AF: 0.00 AC: 0 AN: 86200

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53296

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1109138

Other (OTH) AF: 0.00 AC: 0 AN: 60276

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hermansky-Pudlak syndrome 5 Pathogenic:2

Apr 27, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 01, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

not provided Pathogenic:1

Mar 04, 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.Thr977Argfs*15) 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 T977insGA. ClinVar contains an entry for this variant (Variation ID: 21820). For these reasons, this variant has been classified as Pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.028
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs397507169; hg19: chr11-18306914;