rs201227603
Variant summary
Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PM2PP3_StrongPP5_Very_Strong
The NM_032383.5(HPS3):c.1163+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000477 in 1,612,910 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_032383.5 splice_donor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 22 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HPS3 | NM_032383.5 | c.1163+1G>A | splice_donor_variant | ENST00000296051.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HPS3 | ENST00000296051.7 | c.1163+1G>A | splice_donor_variant | 1 | NM_032383.5 | P1 | |||
HPS3 | ENST00000460120.5 | c.668+1G>A | splice_donor_variant | 2 | |||||
HPS3 | ENST00000462030.5 | n.1762+1G>A | splice_donor_variant, non_coding_transcript_variant | 2 | |||||
HPS3 | ENST00000486530.1 | n.1196+1G>A | splice_donor_variant, non_coding_transcript_variant | 5 |
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152148Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000796 AC: 20AN: 251320Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135824
GnomAD4 exome AF: 0.0000472 AC: 69AN: 1460762Hom.: 0 Cov.: 32 AF XY: 0.0000344 AC XY: 25AN XY: 726740
GnomAD4 genome AF: 0.0000526 AC: 8AN: 152148Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5AN XY: 74330
ClinVar
Submissions by phenotype
Hermansky-Pudlak syndrome 3 Pathogenic:4Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 30, 2022 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 2001 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Nov 03, 2021 | NM_032383.3(HPS3):c.1163+1G>A is a canonical splice variant classified as pathogenic in the context of Hermansky-Pudlak syndrome type 3. Please note that c.1163+1G>A may be associated with a mild form of the disease. c.1163+1G>A has been observed in cases with relevant disease (PMID: 11590544). Functional assessments of this variant are available in the literature (PMID: 11590544). c.1163+1G>A has been observed in population frequency databases (gnomAD: ASJ 0.16%). In summary, NM_032383.3(HPS3):c.1163+1G>A is a canonical splice variant in a gene where loss of function is a known mechanism of disease, has functional support for pathogenicity, and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 25, 2024 | - - |
Hermansky-Pudlak syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 08, 2018 | The c.1163+1G>A variant, also known as c.1303+1G>A, in HPS3 has been reported in the homozygous state in 3 individuals with Hermansky Pudlak syndrome type 3 and in the compound heterozygous state with other splice site variants in 2 individ uals with Hermansky Pudlak syndrome type 3, all of whom had Ashkenazi Jewish anc estry (Huizing 2001). It has also been identified in 0.17% (17/10150) of Ashkena zi Jewish chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence. Stud ies have demonstrated that this variant cases skipping of exon 5, resulting in a premature translational stop at codon 350, which is predicted to produce a trun cated or absent protein (Huizing 2001). Loss of function of the HPS3 gene is an established disease mechanism in Hermansky Pudlak syndrome type 3, which is a mi lder form of Hermansky Pudlak syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Hermansky Pudlak syndrome . ACMG/AMP Criteria applied: PVS1, PM3_Strong, PS3_Supporting. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 18, 2024 | This sequence change affects a donor splice site in intron 5 of the HPS3 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs201227603, gnomAD 0.2%), including at least one homozygous and/or hemizygous individual. Disruption of this splice site has been observed in individuals with Hermansky-Pudlak syndrome (HPS) (PMID: 11590544). It is commonly reported in individuals of Ashkenazi Jewish ancestry (PMID: 11590544). This variant is also known as 1303+1G>A. ClinVar contains an entry for this variant (Variation ID: 4609). Studies have shown that disruption of this splice site results in skipping of exon 5 and introduces a premature termination codon (PMID: 11590544). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Feb 16, 2016 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at