10-102065475-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP5_Moderate

The NM_024747.6(HPS6):​c.1A>T​(p.Met1?) variant causes a initiator codon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000185 in 1,404,054 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

HPS6
NM_024747.6 initiator_codon

Scores

5
5
6

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 1.89
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_pathogenic. Variant got 8 ACMG points.

PVS1
Start lost variant, next in-frame start position is after 6 pathogenic variants. Next in-frame start position is after 678 CDS bases. Genomic position: 102066152. Lost 0.291 part of the original CDS.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 10-102065475-A-T is Pathogenic according to our data. Variant chr10-102065475-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3590152.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HPS6NM_024747.6 linkc.1A>T p.Met1? initiator_codon_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.1A>T p.Met1? initiator_codon_variant Exon 1 of 1 6 NM_024747.6 ENSP00000299238.5 Q86YV9

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000614
AC:
1
AN:
162808
Hom.:
0
AF XY:
0.0000109
AC XY:
1
AN XY:
92020
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000139
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000185
AC:
26
AN:
1404054
Hom.:
0
Cov.:
31
AF XY:
0.0000201
AC XY:
14
AN XY:
696934
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000228
Gnomad4 OTH exome
AF:
0.0000171
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.00000378
ExAC
AF:
0.00000914
AC:
1

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Hermansky-Pudlak syndrome 6 Pathogenic:1
Mar 22, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.20
D
BayesDel_noAF
Uncertain
0.060
CADD
Uncertain
24
DANN
Benign
0.97
DEOGEN2
Benign
0.29
T
Eigen
Uncertain
0.50
Eigen_PC
Uncertain
0.47
FATHMM_MKL
Benign
0.46
N
LIST_S2
Uncertain
0.90
D
M_CAP
Pathogenic
0.84
D
MetaRNN
Pathogenic
0.99
D
MetaSVM
Benign
-0.56
T
PROVEAN
Benign
-1.7
N
REVEL
Uncertain
0.43
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
0.99
D
Vest4
0.57
MutPred
1.0
Loss of MoRF binding (P = 0.1133);
MVP
0.26
ClinPred
0.99
D
GERP RS
4.8
Varity_R
0.95
gMVP
0.49

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: rs763073715; hg19: chr10-103825232; API