rs199816481

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_024747.6(HPS6):c.398C>T(p.Ala133Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00292 in 1,528,316 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0029 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0029 ( 15 hom. )

Consequence

HPS6
NM_024747.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.48

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]

HPS6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0039404333).

BP6

Variant 10-102065872-C-T is Benign according to our data. Variant chr10-102065872-C-T is described in ClinVar as [Benign]. Clinvar id is 298554.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-102065872-C-T is described in Lovd as [Benign]. Variant chr10-102065872-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00294 (448/152254) while in subpopulation NFE AF= 0.00303 (206/68002). AF 95% confidence interval is 0.00269. There are 1 homozygotes in gnomad4. There are 258 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPS6	NM_024747.6 link	c.398C>T	p.Ala133Val	missense_variant	Exon 1 of 1	ENST00000299238.7	NP_079023.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HPS6	ENST00000299238.7 link	c.398C>T	p.Ala133Val	missense_variant	Exon 1 of 1	6	NM_024747.6	ENSP00000299238.5		Q86YV9

Frequencies

GnomAD3 genomes

AF:

0.00294

AC:

448

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.0183

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.00303

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00236

AC:

297

AN:

126038

Hom.:

AF XY:

0.00243

AC XY:

168

AN XY:

69164

show subpopulations

Gnomad AFR exome

AF:

0.000478

Gnomad AMR exome

AF:

0.000464

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00177

Gnomad FIN exome

AF:

0.0166

Gnomad NFE exome

AF:

0.00317

Gnomad OTH exome

AF:

0.00230

GnomAD4 exome

AF:

0.00292

AC:

4015

AN:

1376062

Hom.:

Cov.:

AF XY:

0.00293

AC XY:

1987

AN XY:

678408

show subpopulations

Gnomad4 AFR exome

AF:

0.000382

Gnomad4 AMR exome

AF:

0.000544

Gnomad4 ASJ exome

AF:

0.0000404

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00186

Gnomad4 FIN exome

AF:

0.0186

Gnomad4 NFE exome

AF:

0.00288

Gnomad4 OTH exome

AF:

0.00197

GnomAD4 genome

AF:

0.00294

AC:

448

AN:

152254

Hom.:

Cov.:

AF XY:

0.00347

AC XY:

258

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.000722

Gnomad4 AMR

AF:

0.000588

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.0183

Gnomad4 NFE

AF:

0.00303

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00266

Hom.:

Bravo

AF:

0.00161

ExAC

AF:

0.00152

AC:

137

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 15, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified

Benign:1

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hermansky-Pudlak syndrome 6

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.56

Eigen

Benign

-0.12

Eigen_PC

Benign

-0.036

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.58

MetaRNN

Benign

0.0039

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.5

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-2.5

REVEL

Benign

0.085

Sift

Uncertain

0.023

Sift4G

Uncertain

0.029

Polyphen

0.22

Vest4

0.19

MVP

0.27

MPC

0.49

ClinPred

0.047

GERP RS

4.0

Varity_R

0.11

gMVP

0.41

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over