rs79009787

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

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPS5	NM_181507.2	MANE Select	c.1635-4C>G		splice_region intron	N/A	NP_852608.1
	HPS5	NM_001440902.1		c.1635-4C>G		splice_region intron	N/A	NP_001427831.1
	HPS5	NM_001440903.1		c.1635-4C>G		splice_region intron	N/A	NP_001427832.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPS5	ENST00000349215.8	TSL:1 MANE Select	c.1635-4C>G		splice_region intron	N/A	ENSP00000265967.5
	HPS5	ENST00000396253.7	TSL:1	c.1293-4C>G		splice_region intron	N/A	ENSP00000379552.3
	HPS5	ENST00000438420.6	TSL:1	c.1293-4C>G		splice_region intron	N/A	ENSP00000399590.2

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

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Hermansky-Pudlak syndrome 5 (1)

Computational scores

Source: dbNSFP v4.9

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;