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

Genomes: 𝑓 0.00014 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

HPS6
NM_024747.6 missense

Scores

1
17

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 0.723
Variant links:
Genes affected
HPS6 (HGNC:18817): (HPS6 biogenesis of lysosomal organelles complex 2 subunit 3) This intronless gene encodes a protein that may play a role in organelle biogenesis associated with melanosomes, platelet dense granules, and lysosomes. This protein interacts with Hermansky-Pudlak syndrome 5 protein. Mutations in this gene are associated with Hermansky-Pudlak syndrome type 6. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.005348325).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HPS6NM_024747.6 linkc.254C>T p.Pro85Leu missense_variant Exon 1 of 1 ENST00000299238.7 NP_079023.2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HPS6ENST00000299238.7 linkc.254C>T p.Pro85Leu missense_variant Exon 1 of 1 6 NM_024747.6 ENSP00000299238.5 Q86YV9

Frequencies

GnomAD3 genomes
AF:
0.000138
AC:
21
AN:
151980
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000197
Gnomad ASJ
AF:
0.000288
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000177
Gnomad OTH
AF:
0.00143
GnomAD3 exomes
AF:
0.000340
AC:
34
AN:
100116
Hom.:
0
AF XY:
0.000303
AC XY:
17
AN XY:
56016
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000679
Gnomad ASJ exome
AF:
0.00115
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000243
Gnomad OTH exome
AF:
0.000989
GnomAD4 exome
AF:
0.000139
AC:
188
AN:
1350870
Hom.:
0
Cov.:
31
AF XY:
0.000138
AC XY:
92
AN XY:
666376
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000467
Gnomad4 ASJ exome
AF:
0.000543
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000132
Gnomad4 FIN exome
AF:
0.0000300
Gnomad4 NFE exome
AF:
0.000130
Gnomad4 OTH exome
AF:
0.000284
GnomAD4 genome
AF:
0.000138
AC:
21
AN:
151980
Hom.:
0
Cov.:
33
AF XY:
0.000202
AC XY:
15
AN XY:
74246
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.000197
Gnomad4 ASJ
AF:
0.000288
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000177
Gnomad4 OTH
AF:
0.00143
Alfa
AF:
0.000141
Hom.:
0
Bravo
AF:
0.000117
ExAC
AF:
0.000115
AC:
8

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Uncertain:2
Mar 31, 2017
Genetic Services Laboratory, University of Chicago
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dec 19, 2024
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
Feb 28, 2022
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 24, 2023
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

not provided Uncertain:2
Sep 27, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

May 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

HPS6: PM2:Supporting -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
BayesDel_addAF
Benign
-0.46
T
BayesDel_noAF
Benign
-0.53
CADD
Benign
19
DANN
Benign
0.96
DEOGEN2
Benign
0.34
T
Eigen
Benign
-0.56
Eigen_PC
Benign
-0.48
FATHMM_MKL
Benign
0.057
N
LIST_S2
Benign
0.53
T
MetaRNN
Benign
0.0053
T
MetaSVM
Benign
-0.72
T
MutationAssessor
Benign
1.9
M
PrimateAI
Uncertain
0.68
T
PROVEAN
Benign
-2.1
N
REVEL
Benign
0.081
Sift
Benign
0.17
T
Sift4G
Benign
0.17
T
Polyphen
0.0
B
Vest4
0.16
MVP
0.33
MPC
0.48
ClinPred
0.060
T
GERP RS
2.8
Varity_R
0.050
gMVP
0.33

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs544314793; hg19: chr10-103825485; API