chr11-18295173-G-C

Variant names:

• chr11-18295173-G-C
• rs79009787
• NM_181507.2:c.1635-4C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_181507.2(HPS5):​c.1635-4C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00219 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, intron
• Scores: Splicing: ADA: 0.0004898
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.00800
• Publications: 4 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPS5	NM_181507.2	c.1635-4C>G		splice_region_variant, intron_variant	Intron 13 of 22	ENST00000349215.8	NP_852608.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HPS5	ENST00000349215.8	c.1635-4C>G		splice_region_variant, intron_variant	Intron 13 of 22	1	NM_181507.2	ENSP00000265967.5

Frequencies

GnomAD3 genomes AF: 0.00230 AC: 350 AN: 152128 Hom.: 6 Cov.: 32

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

GnomAD2 exomes AF: 0.00451 AC: 1128 AN: 250336 AF XY: 0.00447

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 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.: 37 Cov.: 31 AF XY: 0.00222 AC XY: 1615 AN XY: 726942

African (AFR) AF: 0.000179 AC: 6 AN: 33474

American (AMR) AF: 0.000605 AC: 27 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.00122 AC: 32 AN: 26126

East Asian (EAS) AF: 0.0371 AC: 1472 AN: 39682

South Asian (SAS) AF: 0.00154 AC: 133 AN: 86214

European-Finnish (FIN) AF: 0.000356 AC: 19 AN: 53320

Middle Eastern (MID) AF: 0.00122 AC: 7 AN: 5754

European-Non Finnish (NFE) AF: 0.00108 AC: 1203 AN: 1111704

Other (OTH) AF: 0.00475 AC: 287 AN: 60370

GnomAD4 genome AF: 0.00229 AC: 349 AN: 152246 Hom.: 6 Cov.: 32 AF XY: 0.00250 AC XY: 186 AN XY: 74436

African (AFR) AF: 0.000265 AC: 11 AN: 41548

American (AMR) AF: 0.00144 AC: 22 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 8 AN: 3472

East Asian (EAS) AF: 0.0435 AC: 225 AN: 5176

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4826

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000926 AC: 63 AN: 68024

Other (OTH) AF: 0.00380 AC: 8 AN: 2104

Alfa AF: 0.00106 Hom.: 0

Bravo AF: 0.00283

Asia WGS AF: 0.0240 AC: 84 AN: 3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 14, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

Hermansky-Pudlak syndrome 5 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		0.0080
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs79009787; hg19: chr11-18316720;