rs369112226
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6
The NM_024747.6(HPS6):c.455C>T(p.Ser152Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000048 in 1,564,072 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_024747.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HPS6 | NM_024747.6 | c.455C>T | p.Ser152Leu | missense_variant | 1/1 | ENST00000299238.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HPS6 | ENST00000299238.7 | c.455C>T | p.Ser152Leu | missense_variant | 1/1 | NM_024747.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000591 AC: 9AN: 152156Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000298 AC: 5AN: 167950Hom.: 0 AF XY: 0.0000320 AC XY: 3AN XY: 93788
GnomAD4 exome AF: 0.0000467 AC: 66AN: 1411800Hom.: 0 Cov.: 31 AF XY: 0.0000471 AC XY: 33AN XY: 699984
GnomAD4 genome ? AF: 0.0000591 AC: 9AN: 152272Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4AN XY: 74452
ClinVar
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 09, 2021 | This sequence change replaces serine with leucine at codon 152 of the HPS6 protein (p.Ser152Leu). The serine residue is weakly conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs369112226, ExAC 0.02%). 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: 163682). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 11, 2013 | Ser152Leu in exon 1 of HPS6: This variant has been identified in 0.01% (1/7512) of European American chromosomes by the NHLBI Exome Sequencing Project (http://e vs.gs.washington.edu/EVS). While this frequency does not rule out a role in dise ase, serine (Ser) at position 152 is poorly conserved in evolution (several mamm als including primates) have a Leucine (Leu) at this position, suggesting that t his change can be tolerated. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at