dbSNP rs201439984: HPS5:c.986-5C>T (chr11-18298975-G-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_181507.2(HPS5):c.986-5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000426 in 1,613,894 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00045 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00042 ( 2 hom. )

Consequence

HPS5
NM_181507.2 splice_region, intron

Scores

Splicing: ADA: 0.00002768

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 0.751

Publications

0 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: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BP6

Variant 11-18298975-G-A is Benign according to our data. Variant chr11-18298975-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 262990.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000447 (68/152284) while in subpopulation SAS AF = 0.00269 (13/4824). AF 95% confidence interval is 0.00159. There are 0 homozygotes in GnomAd4. There are 28 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

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.986-5C>T	splice_region intron	N/A	NP_852608.1	Q9UPZ3-1
HPS5	NM_001440902.1		c.986-5C>T	splice_region intron	N/A	NP_001427831.1
HPS5	NM_001440903.1		c.986-5C>T	splice_region 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.986-5C>T	splice_region intron	N/A	ENSP00000265967.5	Q9UPZ3-1
HPS5	ENST00000396253.7	TSL:1	c.644-5C>T	splice_region intron	N/A	ENSP00000379552.3	Q9UPZ3-2
HPS5	ENST00000438420.6	TSL:1	c.644-5C>T	splice_region intron	N/A	ENSP00000399590.2	Q9UPZ3-2

Frequencies

GnomAD3 genomes

AF:

0.000447

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00979

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.000776

AC:

195

AN:

251344

AF XY:

0.000810

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.00894

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000308

Gnomad OTH exome

AF:

0.00131

GnomAD4 exome

AF:

0.000424

AC:

620

AN:

1461610

Hom.:

Cov.:

AF XY:

0.000461

AC XY:

335

AN XY:

727112

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.000179

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00972

AC:

254

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39688

South Asian (SAS)

AF:

0.00131

AC:

113

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.000158

AC:

176

AN:

1111786

Other (OTH)

AF:

0.00111

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

118

148

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000447

AC:

AN:

152284

Hom.:

Cov.:

AF XY:

0.000376

AC XY:

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41558

American (AMR)

AF:

0.00

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00979

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00269

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000250

AC:

AN:

68024

Other (OTH)

AF:

0.000947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

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:

0.000721

Hom.:

Bravo

AF:

0.000450

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000273

EpiControl

AF:

0.000533

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hermansky-Pudlak syndrome 5 (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

5.4

(source)

DANN

Benign

0.46

PhyloP100

0.75

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000028

dbscSNV1_RF

Benign

0.018

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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