rs786205464

Variant names:

• chr10-98424315-C-T
• rs786205464
• NM_000195.5:c.1395G>A
• HPS1 p.Trp465*

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000195.5(HPS1):​c.1395G>A​(p.Trp465*) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: HPS1 NM_000195.5 stop_gained, splice_region
• Scores: Splicing: ADA: 0.0001447
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 0.0300
• Publications: 3 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: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-98424315-C-T is Pathogenic according to our data. Variant chr10-98424315-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 191013.Status of the report is criteria_provided_single_submitter, 1 stars.

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.1395G>A	p.Trp465*	stop_gained splice_region	Exon 14 of 20	NP_000186.2
	HPS1	NM_001322476.2		c.1395G>A	p.Trp465*	stop_gained splice_region	Exon 14 of 20	NP_001309405.1	Q92902-1
	HPS1	NM_001322477.2		c.1395G>A	p.Trp465*	stop_gained splice_region	Exon 14 of 20	NP_001309406.1	Q92902-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPS1	ENST00000361490.9	TSL:1 MANE Select	c.1395G>A	p.Trp465*	stop_gained splice_region	Exon 14 of 20	ENSP00000355310.4	Q92902-1
	HPS1	ENST00000467246.5	TSL:1	n.*754G>A		splice_region non_coding_transcript_exon	Exon 13 of 19	ENSP00000514163.1	A0A8V8TP71
	ENSG00000289758	ENST00000699159.1		n.*754G>A		splice_region non_coding_transcript_exon	Exon 13 of 24	ENSP00000514167.1	A0A8V8TP71

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	34
DANN	Benign	0.97
Eigen	Benign	-0.0065
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.17	N
PhyloP100		0.030
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=15/185	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00014
dbscSNV1_RF	Benign	0.30
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs786205464;

hg19: chr10-100184072;