Genetic Variant HPS5:c.897-1054A>G (chr11-18301970-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_181507.2(HPS5):c.897-1054A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.726 in 151,840 control chromosomes in the GnomAD database, including 40,474 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.73 ( 40474 hom., cov: 29)

Consequence

HPS5
NM_181507.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.724

Publications

23 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.98).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.946 is higher than 0.05.

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.897-1054A>G	intron	N/A	NP_852608.1	Q9UPZ3-1
HPS5	NM_001440902.1		c.897-1054A>G	intron	N/A	NP_001427831.1
HPS5	NM_001440903.1		c.897-1054A>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.897-1054A>G	intron	N/A	ENSP00000265967.5	Q9UPZ3-1
HPS5	ENST00000396253.7	TSL:1	c.555-1054A>G	intron	N/A	ENSP00000379552.3	Q9UPZ3-2
HPS5	ENST00000438420.6	TSL:1	c.555-1054A>G	intron	N/A	ENSP00000399590.2	Q9UPZ3-2

Frequencies

GnomAD3 genomes

AF:

0.726

AC:

110153

AN:

151722

Hom.:

40426

Cov.:

show subpopulations

Gnomad AFR

AF:

0.764

Gnomad AMI

AF:

0.765

Gnomad AMR

AF:

0.745

Gnomad ASJ

AF:

0.591

Gnomad EAS

AF:

0.969

Gnomad SAS

AF:

0.750

Gnomad FIN

AF:

0.719

Gnomad MID

AF:

0.601

Gnomad NFE

AF:

0.687

Gnomad OTH

AF:

0.710

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.726

AC:

110257

AN:

151840

Hom.:

40474

Cov.:

AF XY:

0.730

AC XY:

54142

AN XY:

74212

show subpopulations

African (AFR)

AF:

0.764

AC:

31614

AN:

41382

American (AMR)

AF:

0.746

AC:

11372

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.591

AC:

2045

AN:

3462

East Asian (EAS)

AF:

0.968

AC:

5001

AN:

5164

South Asian (SAS)

AF:

0.750

AC:

3610

AN:

4814

European-Finnish (FIN)

AF:

0.719

AC:

7571

AN:

10524

Middle Eastern (MID)

AF:

0.588

AC:

173

AN:

294

European-Non Finnish (NFE)

AF:

0.687

AC:

46671

AN:

67928

Other (OTH)

AF:

0.713

AC:

1505

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1465

2930

4395

5860

7325

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

828

1656

2484

3312

4140

<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:

0.699

Hom.:

113277

Bravo

AF:

0.732

Asia WGS

AF:

0.889

AC:

3086

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.98

CADD

Benign

9.1

(source)

DANN

Benign

0.74

PhyloP100

-0.72

Mutation Taster

=100/0

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over