rs79009787

Positions:

chr11-18295173-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_181507.2(HPS5):c.1635-4C>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00219 in 1,613,552 control chromosomes in the GnomAD database, including 43 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0023 ( 6 hom., cov: 32)

Exomes 𝑓: 0.0022 ( 37 hom. )

Consequence

HPS5
NM_181507.2 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.0004898

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.00800

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.77).

BP6

Variant 11-18295173-G-C is Benign according to our data. Variant chr11-18295173-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 226661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00229 (349/152246) while in subpopulation EAS AF= 0.0435 (225/5176). AF 95% confidence interval is 0.0388. There are 6 homozygotes in gnomad4. There are 186 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HPS5	NM_181507.2 linkuse as main transcript	c.1635-4C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000349215.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HPS5	ENST00000349215.8 linkuse as main transcript	c.1635-4C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_181507.2	P1	Q9UPZ3-1

Frequencies

GnomAD3 genomes

AF:

0.00230

AC:

350

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000266

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00144

Gnomad ASJ

AF:

0.00230

Gnomad EAS

AF:

0.0438

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000926

Gnomad OTH

AF:

0.00384

GnomAD3 exomes

AF:

0.00451

AC:

1128

AN:

250336

Hom.:

AF XY:

0.00447

AC XY:

605

AN XY:

135320

show subpopulations

Gnomad AFR exome

AF:

0.000247

Gnomad AMR exome

AF:

0.000435

Gnomad ASJ exome

AF:

0.00159

Gnomad EAS exome

AF:

0.0484

Gnomad SAS exome

AF:

0.00196

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.00111

Gnomad OTH exome

AF:

0.00327

GnomAD4 exome

AF:

0.00218

AC:

3186

AN:

1461306

Hom.:

Cov.:

AF XY:

0.00222

AC XY:

1615

AN XY:

726942

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.000605

Gnomad4 ASJ exome

AF:

0.00122

Gnomad4 EAS exome

AF:

0.0371

Gnomad4 SAS exome

AF:

0.00154

Gnomad4 FIN exome

AF:

0.000356

Gnomad4 NFE exome

AF:

0.00108

Gnomad4 OTH exome

AF:

0.00475

GnomAD4 genome

AF:

0.00229

AC:

349

AN:

152246

Hom.:

Cov.:

AF XY:

0.00250

AC XY:

186

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.000265

Gnomad4 AMR

AF:

0.00144

Gnomad4 ASJ

AF:

0.00230

Gnomad4 EAS

AF:

0.0435

Gnomad4 SAS

AF:

0.00166

Gnomad4 FIN

AF:

0.000377

Gnomad4 NFE

AF:

0.000926

Gnomad4 OTH

AF:

0.00380

Alfa

AF:

0.00106

Hom.:

Bravo

AF:

0.00283

Asia WGS

AF:

0.0240

AC:

AN:

3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	1635-4C>G in intron 13 of HPS5: This variant is not expected to have clinical si gnificance because it is not located within the conserved splice consensus seque nce. It has been identified in 6.7% (13/194) of Han Chinese chromosomes from a b road population by the 1000 Genomes Project (http://www.ncbi.nlm.nih.gov/project s/SNP; dbSNP rs79009787). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 14, 2021	See Variant Classification Assertion Criteria. -

Hermansky-Pudlak syndrome 5

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

3.7

DANN

Benign

0.62

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00049

dbscSNV1_RF

Benign

0.0060

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over