rs11591594

Variant names:

• chr10-98434126-C-T
• rs11591594
• NM_000195.5:c.399-35G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000195.5(HPS1):​c.399-35G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.16 in 1,538,246 control chromosomes in the GnomAD database, including 20,789 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.13 (1516 hom., cov: 31)
  • Exomes 𝑓: 0.16 (19273 hom.)
• Consequence: HPS1 NM_000195.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.39
• Publications: 4 publications found

Genes affected

HPS1 (HGNC:5163): (HPS1 biogenesis of lysosomal organelles complex 3 subunit 1) This gene encodes a protein that may play a role in organelle biogenesis associated with melanosomes, platelet dense granules, and lysosomes. The encoded protein is a component of three different protein complexes termed biogenesis of lysosome-related organelles complex (BLOC)-3, BLOC4, and BLOC5. Mutations in this gene are associated with Hermansky-Pudlak syndrome type 1. Alternative splicing results in multiple transcript variants. A pseudogene related to this gene is located on chromosome 22. [provided by RefSeq, Aug 2015]

HPS1 Gene-Disease associations (from GenCC):

• Hermansky-Pudlak syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• Hermansky-Pudlak syndrome with pulmonary fibrosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000289758 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 0 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 10-98434126-C-T is Benign according to our data. Variant chr10-98434126-C-T is described in ClinVar as Benign. ClinVar VariationId is 255503.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.206 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000195.5. 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
	HPS1	NM_000195.5	MANE Select	c.399-35G>A		intron	N/A	NP_000186.2
	HPS1	NM_001322476.2		c.399-35G>A		intron	N/A	NP_001309405.1
	HPS1	NM_001322477.2		c.399-35G>A		intron	N/A	NP_001309406.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPS1	ENST00000361490.9	TSL:1 MANE Select	c.399-35G>A		intron	N/A	ENSP00000355310.4
	HPS1	ENST00000338546.9	TSL:1	c.399-35G>A		intron	N/A	ENSP00000343638.5
	HPS1	ENST00000467246.5	TSL:1	n.399-35G>A		intron	N/A	ENSP00000514163.1

Frequencies

GnomAD3 genomes AF: 0.128 AC: 19501 AN: 152004 Hom.: 1518 Cov.: 31

Gnomad AFR AF: 0.0609

Gnomad AMI AF: 0.113

Gnomad AMR AF: 0.0925

Gnomad ASJ AF: 0.109

Gnomad EAS AF: 0.107

Gnomad SAS AF: 0.218

Gnomad FIN AF: 0.167

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.168

Gnomad OTH AF: 0.125

GnomAD2 exomes AF: 0.143 AC: 20465 AN: 142816 AF XY: 0.151

Gnomad AFR exome AF: 0.0537

Gnomad AMR exome AF: 0.0702

Gnomad ASJ exome AF: 0.111

Gnomad EAS exome AF: 0.117

Gnomad FIN exome AF: 0.177

Gnomad NFE exome AF: 0.167

Gnomad OTH exome AF: 0.139

GnomAD4 exome AF: 0.163 AC: 226344 AN: 1386124 Hom.: 19273 Cov.: 32 AF XY: 0.165 AC XY: 112852 AN XY: 683668

African (AFR) AF: 0.0556 AC: 1750 AN: 31492

American (AMR) AF: 0.0717 AC: 2550 AN: 35572

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 2805 AN: 25082

East Asian (EAS) AF: 0.0879 AC: 3131 AN: 35638

South Asian (SAS) AF: 0.202 AC: 15958 AN: 78864

European-Finnish (FIN) AF: 0.177 AC: 7293 AN: 41092

Middle Eastern (MID) AF: 0.118 AC: 593 AN: 5014

European-Non Finnish (NFE) AF: 0.170 AC: 183354 AN: 1075698

Other (OTH) AF: 0.154 AC: 8910 AN: 57672

GnomAD4 genome AF: 0.128 AC: 19504 AN: 152122 Hom.: 1516 Cov.: 31 AF XY: 0.129 AC XY: 9562 AN XY: 74344

African (AFR) AF: 0.0609 AC: 2525 AN: 41492

American (AMR) AF: 0.0924 AC: 1412 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.109 AC: 378 AN: 3472

East Asian (EAS) AF: 0.108 AC: 556 AN: 5172

South Asian (SAS) AF: 0.217 AC: 1045 AN: 4810

European-Finnish (FIN) AF: 0.167 AC: 1765 AN: 10576

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.168 AC: 11411 AN: 67990

Other (OTH) AF: 0.127 AC: 269 AN: 2116

Alfa AF: 0.142 Hom.: 390

Bravo AF: 0.117

Asia WGS AF: 0.140 AC: 484 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.2
DANN	Benign	0.44
PhyloP100		-1.4
BranchPoint Hunter		0.0
PromoterAI		-0.015	Neutral
RBP_binding_hub_radar		0.67
RBP_regulation_power_radar		1.8
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11591594; hg19: chr10-100193883;