chr10-102065710-T-TG
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_StrongPM2PP5
The NM_024747.6(HPS6):c.238dupG(p.Asp80GlyfsTer96) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000749 in 1,507,968 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_024747.6 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
HPS6 | NM_024747.6 | c.238dupG | p.Asp80GlyfsTer96 | frameshift_variant | Exon 1 of 1 | ENST00000299238.7 | NP_079023.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000461 AC: 7AN: 151874Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000192 AC: 2AN: 104412Hom.: 0 AF XY: 0.0000171 AC XY: 1AN XY: 58448
GnomAD4 exome AF: 0.0000782 AC: 106AN: 1356094Hom.: 0 Cov.: 31 AF XY: 0.0000762 AC XY: 51AN XY: 669278
GnomAD4 genome AF: 0.0000461 AC: 7AN: 151874Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74194
ClinVar
Submissions by phenotype
Hermansky-Pudlak syndrome 6 Pathogenic:3Uncertain:1
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The HPS6 c.238dupG (p.Asp80GlyfsTer96) variant results in a frameshift and is predicted to result in premature termination of the protein. The p.Asp80GlyfsTer96 variant has been reported in one study in which it is identified in a compound heterozygous state with a missense variant in one individual diagnosed with Hermansky- Pudlak syndrome (Huizing et al. 2009). Control data are unavailable for this variant which is not found in the 1000 Genomes Project, the Exome Sequencing Project, Exome Aggregation Consortium, or the Genome Aggregation Database. Based on the limited clinical evidence and potential impact of frameshift variants, the c.238dupG (p.Asp80GlyfsTer96) variant is classified as a variant of unknown significance but suspicious for pathogenicity for Hermansky-Pudlak syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
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The p.Asp80GlyfsX96 variant in HPS6 has been reported in 1 compound heterozygous individual with clinical features of Hermansky-Pudlak syndrome (Huizing 2009). Data from large population studies is insufficient to assess the frequency of this variant. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 80 and leads to a premature termination codon 96 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Truncating HPS6 variants have been identified in several homozygous and compound heterozygous individuals with Hermansky-Pudlak syndrome (Zhang 2003, Huizing 2009). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. -
not provided Pathogenic:1Uncertain:1
This sequence change creates a premature translational stop signal (p.Asp80Glyfs*96) in the HPS6 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 696 amino acid(s) of the HPS6 protein. 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 premature translational stop signal has been observed in individual(s) with Hermansky-Pudlak syndrome (PMID: 19843503). ClinVar contains an entry for this variant (Variation ID: 208586). This variant disrupts a region of the HPS6 protein in which other variant(s) (p.Leu356Alafs*11) have been determined to be pathogenic (PMID: 17041891). 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. -
Observed with a second HPS6 variant in patients with features suggestive of Hermansky-Pudlak syndrome in published literature, but detailed clinical information and additional genetic testing results were not provided in some cases (PMID: 19843503, 31064749, 33612058); Frameshift variant predicted to result in abnormal protein length as the last 696 amino acids are replaced with 95 different amino acids, and other similar variants have been reported in HGMD; This variant is associated with the following publications: (PMID: 30369044, 12548288, 17041891, 38091959, 31064749, 33612058, 31898847, 19843503) -
Hermansky-Pudlak syndrome Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at