chr11-18305438-T-TG

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_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

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 0.741

Publications

3 publications found

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 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

HPS5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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 CliVar as Pathogenic. Clinvar id is 21822.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-18305438-T-TG is described in CliVar as Pathogenic. Clinvar id is 21822.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-18305438-T-TG is described in CliVar as Pathogenic. Clinvar id is 21822.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-18305438-T-TG is described in CliVar as Pathogenic. Clinvar id is 21822.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-18305438-T-TG is described in CliVar as Pathogenic. Clinvar id is 21822.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-18305438-T-TG is described in CliVar as Pathogenic. Clinvar id is 21822.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-18305438-T-TG is described in CliVar as Pathogenic. Clinvar id is 21822.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-18305438-T-TG is described in CliVar as Pathogenic. Clinvar id is 21822.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-18305438-T-TG is described in CliVar as Pathogenic. Clinvar id is 21822.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-18305438-T-TG is described in CliVar as Pathogenic. Clinvar id is 21822.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-18305438-T-TG is described in CliVar as Pathogenic. Clinvar id is 21822.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-18305438-T-TG is described in CliVar as Pathogenic. Clinvar id is 21822.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-18305438-T-TG is described in CliVar as Pathogenic. Clinvar id is 21822.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-18305438-T-TG is described in CliVar as Pathogenic. Clinvar id is 21822.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-18305438-T-TG is described in CliVar as Pathogenic. Clinvar id is 21822.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-18305438-T-TG is described in CliVar as Pathogenic. Clinvar id is 21822.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-18305438-T-TG is described in CliVar as Pathogenic. Clinvar id is 21822.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-18305438-T-TG is described in CliVar as Pathogenic. Clinvar id is 21822.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-18305438-T-TG is described in CliVar as Pathogenic. Clinvar id is 21822.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-18305438-T-TG is described in CliVar as Pathogenic. Clinvar id is 21822.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-18305438-T-TG is described in CliVar as Pathogenic. Clinvar id is 21822.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-18305438-T-TG is described in CliVar as Pathogenic. Clinvar id is 21822.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-18305438-T-TG is described in CliVar as Pathogenic. Clinvar id is 21822.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-18305438-T-TG is described in CliVar as Pathogenic. Clinvar id is 21822.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-18305438-T-TG is described in CliVar as Pathogenic. Clinvar id is 21822.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-18305438-T-TG is described in CliVar as Pathogenic. Clinvar id is 21822.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-18305438-T-TG is described in CliVar as Pathogenic. Clinvar id is 21822.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-18305438-T-TG is described in CliVar as Pathogenic. Clinvar id is 21822.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-18305438-T-TG is described in CliVar as Pathogenic. Clinvar id is 21822.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-18305438-T-TG is described in CliVar as Pathogenic. Clinvar id is 21822.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-18305438-T-TG is described in CliVar as Pathogenic. Clinvar id is 21822.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-18305438-T-TG is described in CliVar as Pathogenic. Clinvar id is 21822.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-18305438-T-TG is described in CliVar as Pathogenic. Clinvar id is 21822.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-18305438-T-TG is described in CliVar as Pathogenic. Clinvar id is 21822.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-18305438-T-TG is described in CliVar as Pathogenic. Clinvar id is 21822.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-18305438-T-TG is described in CliVar as Pathogenic. Clinvar id is 21822.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-18305438-T-TG is described in CliVar as Pathogenic. Clinvar id is 21822.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-18305438-T-TG is described in CliVar as Pathogenic. Clinvar id is 21822.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-18305438-T-TG is described in CliVar as Pathogenic. Clinvar id is 21822.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-18305438-T-TG is described in CliVar 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 link	c.879dupC	p.Lys294GlnfsTer6	frameshift_variant	Exon 8 of 23	ENST00000349215.8	NP_852608.1	Q9UPZ3-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HPS5	ENST00000349215.8 link	c.879dupC	p.Lys294GlnfsTer6	frameshift_variant	Exon 8 of 23	1	NM_181507.2	ENSP00000265967.5	Q9UPZ3-1
HPS5	ENST00000396253.7 link	c.537dupC	p.Lys180GlnfsTer6	frameshift_variant	Exon 7 of 22	1		ENSP00000379552.3	Q9UPZ3-2
HPS5	ENST00000438420.6 link	c.537dupC	p.Lys180GlnfsTer6	frameshift_variant	Exon 7 of 22	1		ENSP00000399590.2	Q9UPZ3-2
HPS5	ENST00000531848.1 link	c.537dupC	p.Lys180GlnfsTer6	frameshift_variant	Exon 7 of 11	5		ENSP00000431758.1	G3V159

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1455752

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

724652

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33334

American (AMR)

AF:

0.00

AC:

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26086

East Asian (EAS)

AF:

0.00

AC:

AN:

39606

South Asian (SAS)

AF:

0.00

AC:

AN:

86094

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53332

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00000271

AC:

AN:

1106686

Other (OTH)

AF:

0.00

AC:

AN:

60158

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.408

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

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‚ÄìPudlak 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

PhyloP100

0.74

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over