rs121908385

Variant names:

• chr10-98417671-C-A
• rs121908385
• NM_000195.5:c.1996G>T

Your query was ambiguous. Multiple possible variants found:

• chr10-98417671-C-A
• chr10-98417671-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_000195.5(HPS1):​c.1996G>T​(p.Glu666*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: HPS1 NM_000195.5 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.53
• Publications: 6 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: Labcorp Genetics (formerly Invitae), ClinGen, G2P
• Hermansky-Pudlak syndrome with pulmonary fibrosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000289758 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 7 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-98417671-C-A is Pathogenic according to our data. Variant chr10-98417671-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 5279.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.1996G>T	p.Glu666*	stop_gained	Exon 20 of 20	NP_000186.2
	HPS1	NM_001322476.2		c.1996G>T	p.Glu666*	stop_gained	Exon 20 of 20	NP_001309405.1	Q92902-1
	HPS1	NM_001322477.2		c.1996G>T	p.Glu666*	stop_gained	Exon 20 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.1996G>T	p.Glu666*	stop_gained	Exon 20 of 20	ENSP00000355310.4	Q92902-1
	HPS1	ENST00000467246.5	TSL:1	n.*1355G>T		non_coding_transcript_exon	Exon 19 of 19	ENSP00000514163.1	A0A8V8TP71
	HPS1	ENST00000467246.5	TSL:1	n.*1355G>T		3_prime_UTR	Exon 19 of 19	ENSP00000514163.1	A0A8V8TP71

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Hermansky-Pudlak syndrome (1)
1	-	-	Hermansky-Pudlak syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	41
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Uncertain	0.96	D
PhyloP100		7.5
Vest4		0.83
GERP RS		5.5
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs121908385; hg19: chr10-100177428;