10-98427239-GC-GCC

Position:

• chr10-98427239-GC-GCC

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000195.5(HPS1):​c.962dupG​(p.Thr322fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,398,412 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HPS1 NM_000195.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 0.920

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]

ENSG00000289758 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 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 10-98427239-G-GC is Pathogenic according to our data. Variant chr10-98427239-G-GC is described in ClinVar as [Pathogenic]. Clinvar id is 5282.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HPS1	NM_000195.5	c.962dupG	p.Thr322fs	frameshift_variant	11/20	ENST00000361490.9	NP_000186.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HPS1	ENST00000361490.9	c.962dupG	p.Thr322fs	frameshift_variant	11/20	1	NM_000195.5	ENSP00000355310.4
ENSG00000289758	ENST00000699159.1	n.*321dupG		non_coding_transcript_exon_variant	10/24			ENSP00000514167.1
ENSG00000289758	ENST00000699159.1	n.*321dupG		3_prime_UTR_variant	10/24			ENSP00000514167.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1398412 Hom.: 0 Cov.: 30 AF XY: 0.00000145 AC XY: 1 AN XY: 689788

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000558

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hermansky-Pudlak syndrome 1 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jun 15, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 30, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2000	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 20, 2022

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 5282). This premature translational stop signal has been observed in individual(s) with Hermansky-Pudlak syndrome (PMID: 10971344). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Thr322Hisfs*131) in the HPS1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HPS1 are known to be pathogenic (PMID: 12442288, 16185271). -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs281865081; hg19: chr10-100186996;