10-102065728-C-T
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_024747.6(HPS6):c.254C>T(p.Pro85Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000139 in 1,502,850 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P85R) has been classified as Uncertain significance.
Frequency
Consequence
NM_024747.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
HPS6 | NM_024747.6 | c.254C>T | p.Pro85Leu | missense_variant | Exon 1 of 1 | ENST00000299238.7 | NP_079023.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000138 AC: 21AN: 151980Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000340 AC: 34AN: 100116Hom.: 0 AF XY: 0.000303 AC XY: 17AN XY: 56016
GnomAD4 exome AF: 0.000139 AC: 188AN: 1350870Hom.: 0 Cov.: 31 AF XY: 0.000138 AC XY: 92AN XY: 666376
GnomAD4 genome AF: 0.000138 AC: 21AN: 151980Hom.: 0 Cov.: 33 AF XY: 0.000202 AC XY: 15AN XY: 74246
ClinVar
Submissions by phenotype
not specified Uncertain:2
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Variant summary: HPS6 c.254C>T (p.Pro85Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00034 in 100116 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in HPS6 causing Hermansky-Pudlak Syndrome (0.00034 vs 0.00063), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.254C>T in individuals affected with Hermansky-Pudlak Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 435463). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Hermansky-Pudlak syndrome 6 Uncertain:2
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not provided Uncertain:2
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 85 of the HPS6 protein (p.Pro85Leu). This variant is present in population databases (rs544314793, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with HPS6-related conditions. ClinVar contains an entry for this variant (Variation ID: 435463). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt HPS6 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
HPS6: PM2:Supporting -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at