Variant 11-18306136-TGAGAG-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_181507.2(HPS5):c.818_822del(p.Thr273LysfsTer7) variant causes a frameshift, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000138 in 1,444,842 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: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

HPS5
NM_181507.2 frameshift, splice_region

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 3.35

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 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 11-18306136-TGAGAG-T is Pathogenic according to our data. Variant chr11-18306136-TGAGAG-T is described in ClinVar as [Pathogenic]. Clinvar id is 427878.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HPS5	NM_181507.2 linkuse as main transcript	c.818_822del	p.Thr273LysfsTer7	frameshift_variant, splice_region_variant	7/23	ENST00000349215.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HPS5	ENST00000349215.8 linkuse as main transcript	c.818_822del	p.Thr273LysfsTer7	frameshift_variant, splice_region_variant	7/23	1	NM_181507.2	P1	Q9UPZ3-1
HPS5	ENST00000396253.7 linkuse as main transcript	c.476_480del	p.Thr159LysfsTer7	frameshift_variant, splice_region_variant	6/22	1			Q9UPZ3-2
HPS5	ENST00000438420.6 linkuse as main transcript	c.476_480del	p.Thr159LysfsTer7	frameshift_variant, splice_region_variant	6/22	1			Q9UPZ3-2
HPS5	ENST00000531848.1 linkuse as main transcript	c.476_480del	p.Thr159LysfsTer7	frameshift_variant, splice_region_variant	6/11	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251370

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135860

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000138

AC:

AN:

1444842

Hom.:

AF XY:

0.0000125

AC XY:

AN XY:

720052

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000182

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hermansky-Pudlak syndrome 5

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Laboratoire de Génétique Moléculaire, CHU Bordeaux

Mar 14, 2017

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

This sequence change creates a premature translational stop signal (p.Thr273Lysfs*7) 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 (no rsID available, gnomAD 0.0009%). This premature translational stop signal has been observed in individuals with Hermansky-Pudlak syndrome (PMID: 28640947). ClinVar contains an entry for this variant (Variation ID: 427878). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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