10-102065523-G-GGCGGC
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_024747.6(HPS6):c.60_64dupGCGGC(p.Leu22ArgfsTer33) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000895 in 1,552,790 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_024747.6 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
HPS6 | NM_024747.6 | c.60_64dupGCGGC | p.Leu22ArgfsTer33 | frameshift_variant | Exon 1 of 1 | ENST00000299238.7 | NP_079023.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152148Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000192 AC: 3AN: 155942Hom.: 0 AF XY: 0.0000114 AC XY: 1AN XY: 88050
GnomAD4 exome AF: 0.0000935 AC: 131AN: 1400534Hom.: 0 Cov.: 31 AF XY: 0.0000878 AC XY: 61AN XY: 694778
GnomAD4 genome AF: 0.0000525 AC: 8AN: 152256Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74450
ClinVar
Submissions by phenotype
not provided Pathogenic:2
This sequence change creates a premature translational stop signal (p.Leu22Argfs*33) in the HPS6 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 754 amino acid(s) of the HPS6 protein. This variant is present in population databases (rs752399257, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with Hermansky–Pudlak syndrome (PMID: 27593200, 29054114, 30990103). This variant is also known as c.64_65insGCGGC. ClinVar contains an entry for this variant (Variation ID: 1452276). This variant disrupts a region of the HPS6 protein in which other variant(s) (p.Q680*) have been determined to be pathogenic (PMID: 27225848). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Frameshift variant predicted to result in abnormal protein length as the last 754 amino acids are replaced with 32 different amino acids, and other similar variants have been reported in HGMD; This variant is associated with the following publications: (PMID: 30990103, 33878481, 27593200, 29054114, 27535533, 35644009, 38091959, 32725903) -
HPS6-related disorder Pathogenic:1
The HPS6 c.60_64dup5 variant is predicted to result in a frameshift and premature protein termination (p.Leu22Argfs*33). This variant has been reported in the homozygous and compound heterozygous states in individuals with Hermansky-Pudlak syndrome 6 (reported as c.65_65insGCGGC in Wei et al 2016. PubMed ID: 27593200; Okamura et al. 2017. PubMed ID: 29054114; Bastida et al. 2019. PubMed ID: 30990103). This variant is reported in 0.0036% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/10-103825280-G-GGCGGC). Frameshift variants in HPS6 are expected to be pathogenic. Given the evidence, we interpret c.60_64dup (p.Leu22Argfs*33) as pathogenic. -
Hermansky-Pudlak syndrome Pathogenic:1
Variant summary: HPS6 c.60_64dupGCGGC (p.Leu22ArgfsX33) results in a frameshift and premature termination codon, predicted to cause a truncation of the encoded protein, a commonly known mechanism for disease. The variant allele was found at a frequency of 1.9e-05 in 155942 control chromosomes (gnomAD). c.60_64dupGCGGC has been reported in the literature as a biallelic genotype in multiple individuals affected with Hermansky-Pudlak Syndrome (e.g. Wei_2016, Okamura_2018, Bastida_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted a clinical-significance assessment for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at