11-18310943-T-C

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PS3PP3PP5

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). ClinVar reports functional evidence for this variant: "SCV001981927: Published functional studies demonstrate a damaging effect, with reduced levels of mRNA and protein compared to controls and mislocalization of lysosomal markers (PMID:28296950)" and additional evidence is available in ClinVar.

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, ClinGen, Labcorp Genetics (formerly Invitae)
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: Likely_pathogenic. The variant received 6 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV001981927: Published functional studies demonstrate a damaging effect, with reduced levels of mRNA and protein compared to controls and mislocalization of lysosomal markers (PMID: 28296950); SCV005381007: At least one publication reports experimental evidence that this variant affects mRNA splicing (Stephen_2017) resulting in an inframe insertion of 3 amino acids. PMID: 28296950

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.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HPS5	NM_181507.2	MANE Select	c.285-10A>G	intron	N/A	NP_852608.1	Q9UPZ3-1
HPS5	NM_001440902.1		c.285-10A>G	intron	N/A	NP_001427831.1
HPS5	NM_001440903.1		c.285-10A>G	intron	N/A	NP_001427832.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HPS5	ENST00000349215.8	TSL:1 MANE Select	c.285-10A>G	intron	N/A	ENSP00000265967.5	Q9UPZ3-1
HPS5	ENST00000396253.7	TSL:1	c.-58-10A>G	intron	N/A	ENSP00000379552.3	Q9UPZ3-2
HPS5	ENST00000438420.6	TSL:1	c.-58-10A>G	intron	N/A	ENSP00000399590.2	Q9UPZ3-2

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

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hermansky-Pudlak syndrome 5 (2)

not provided (2)

Hermansky-Pudlak syndrome (1)

Computational scores

Source: dbNSFP v4.9

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over