3-149129738-C-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_032383.5(HPS3):​c.15C>A​(p.Tyr5*) variant causes a stop gained 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. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Consequence

HPS3
NM_032383.5 stop_gained

Scores

2
4
1

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 1.50
Variant links:
Genes affected
HPS3 (HGNC:15597): (HPS3 biogenesis of lysosomal organelles complex 2 subunit 1) This gene encodes a protein containing a potential clathrin-binding motif, consensus dileucine signals, and tyrosine-based sorting signals for targeting to vesicles of lysosomal lineage. The encoded protein may play a role in organelle biogenesis associated with melanosomes, platelet dense granules, and lysosomes. Mutations in this gene are associated with Hermansky-Pudlak syndrome type 3. [provided by RefSeq, Apr 2015]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 130 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 3-149129738-C-A is Pathogenic according to our data. Variant chr3-149129738-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 3662719.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HPS3NM_032383.5 linkc.15C>A p.Tyr5* stop_gained Exon 1 of 17 ENST00000296051.7 NP_115759.2 Q969F9-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HPS3ENST00000296051.7 linkc.15C>A p.Tyr5* stop_gained Exon 1 of 17 1 NM_032383.5 ENSP00000296051.2 Q969F9-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Aug 17, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Tyr5*) in the HPS3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HPS3 are known to be pathogenic (PMID: 11590544). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Hermansky-Pudlak syndrome (PMID: 31898847, 35886065). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.60
CADD
Pathogenic
36
DANN
Uncertain
1.0
Eigen
Uncertain
0.59
Eigen_PC
Uncertain
0.42
FATHMM_MKL
Uncertain
0.93
D
Vest4
0.67
GERP RS
3.6

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-148847525; API