11-18310943-T-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3PP5

The NM_181507.2(HPS5):c.285-10A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000285 in 1,613,554 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

HPS5
NM_181507.2 intron

Scores

Splicing: ADA: 0.9992

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:2

Conservation

PhyloP100: -0.168

Publications

2 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: Uncertain_significance. The variant received 2 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 11-18310943-T-C is Pathogenic according to our data. Variant chr11-18310943-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 431165.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPS5	NM_181507.2 link	c.285-10A>G		intron_variant	Intron 4 of 22	ENST00000349215.8	NP_852608.1	Q9UPZ3-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
HPS5	ENST00000349215.8 link	c.285-10A>G	intron_variant	Intron 4 of 22	1	NM_181507.2	ENSP00000265967.5	Q9UPZ3-1
HPS5	ENST00000396253.7 link	c.-58-10A>G	intron_variant	Intron 3 of 21	1		ENSP00000379552.3	Q9UPZ3-2
HPS5	ENST00000438420.6 link	c.-58-10A>G	intron_variant	Intron 3 of 21	1		ENSP00000399590.2	Q9UPZ3-2
HPS5	ENST00000531848.1 link	c.-58-10A>G	intron_variant	Intron 3 of 10	5		ENSP00000431758.1	G3V159

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000384

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000881

AC:

AN:

249608

AF XY:

0.0000889

show subpopulations

Gnomad AFR exome

AF:

0.0000620

Gnomad AMR exome

AF:

0.000434

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000178

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000253

AC:

AN:

1461220

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

726980

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33468

American (AMR)

AF:

0.000358

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39690

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86240

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53372

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000117

AC:

AN:

1111466

Other (OTH)

AF:

0.0000663

AC:

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

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

AF:

0.0000591

AC:

AN:

152334

Hom.:

Cov.:

AF XY:

0.0000671

AC XY:

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41578

American (AMR)

AF:

0.000131

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.000385

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.531

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000658

Hom.:

Bravo

AF:

0.0000340

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hermansky-Pudlak syndrome 5

Pathogenic:1Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Aug 02, 2017

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Pathogenic:1Uncertain:1

Jul 06, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change falls in intron 4 of the HPS5 gene. It does not directly change the encoded amino acid sequence of the HPS5 protein. RNA analysis indicates that this variant induces altered splicing and likely results in the gain of 3 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is present in population databases (rs200449378, gnomAD 0.04%). This variant has been observed in individual(s) with Hermansky-Pudlak syndrome (PMID: 28296950). ClinVar contains an entry for this variant (Variation ID: 431165). Studies have shown that this variant results in the activation of a cryptic splice site in intron 4 (PMID: 28296950). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Mar 03, 2022

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect, with reduced levels of mRNA and protein compared to controls and mislocalization of lysosomal markers (Stephen et al., 2017); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 28640947, 28296950, 29090612) -

Hermansky-Pudlak syndrome

Pathogenic:1

Aug 15, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: HPS5 c.285-10A>G alters a nucleotide located at a position not widely known to affect splicing. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 3' acceptor site. One predict the variant weakens a 3' acceptor site. Three predict the variant creates a 3' acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Stephen_2017) resulting in an inframe insertion of 3 amino acids. The variant allele was found at a frequency of 8.8e-05 in 249608 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in HPS5 causing Hermansky-Pudlak Syndrome (8.8e-05 vs 0.00047), allowing no conclusion about variant significance. c.285-10A>G has been reported in the literature in individuals affected with Hermansky-Pudlak Syndrome (Stephen_2017). The following publication have been ascertained in the context of this evaluation (PMID: 28296950). ClinVar contains an entry for this variant (Variation ID: 431165). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.66

CADD

Benign

(source)

DANN

Benign

0.74

PhyloP100

-0.17

Mutation Taster

=17/83

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

0.71

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.49

Position offset: -1

DS_AL_spliceai

0.71

Position offset: -10

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over