rs36078476

Positions:

chr10-102066172-T-G

Variant summary

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

The NM_024747.6(HPS6):c.698T>G(p.Leu233Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00813 in 1,613,776 control chromosomes in the GnomAD database, including 86 homozygotes. 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0062 ( 11 hom., cov: 33)

Exomes 𝑓: 0.0083 ( 75 hom. )

Consequence

HPS6
NM_024747.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.50

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=0.0056492984).

BP6

Variant 10-102066172-T-G is Benign according to our data. Variant chr10-102066172-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 211155.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0062 (944/152324) while in subpopulation SAS AF= 0.0147 (71/4830). AF 95% confidence interval is 0.012. There are 11 homozygotes in gnomad4. There are 439 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HPS6	NM_024747.6 linkuse as main transcript	c.698T>G	p.Leu233Arg	missense_variant	1/1	ENST00000299238.7	NP_079023.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HPS6	ENST00000299238.7 linkuse as main transcript	c.698T>G	p.Leu233Arg	missense_variant	1/1		NM_024747.6	ENSP00000299238	P1

Frequencies

GnomAD3 genomes

AF:

0.00621

AC:

945

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00157

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.00936

Gnomad ASJ

AF:

0.0259

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0147

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00805

Gnomad OTH

AF:

0.00860

GnomAD3 exomes

AF:

0.00748

AC:

1873

AN:

250234

Hom.:

AF XY:

0.00814

AC XY:

1104

AN XY:

135574

show subpopulations

Gnomad AFR exome

AF:

0.00175

Gnomad AMR exome

AF:

0.00460

Gnomad ASJ exome

AF:

0.0299

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0123

Gnomad FIN exome

AF:

0.000232

Gnomad NFE exome

AF:

0.00839

Gnomad OTH exome

AF:

0.00900

GnomAD4 exome

AF:

0.00833

AC:

12177

AN:

1461452

Hom.:

Cov.:

AF XY:

0.00843

AC XY:

6129

AN XY:

727040

show subpopulations

Gnomad4 AFR exome

AF:

0.00143

Gnomad4 AMR exome

AF:

0.00503

Gnomad4 ASJ exome

AF:

0.0306

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0119

Gnomad4 FIN exome

AF:

0.000340

Gnomad4 NFE exome

AF:

0.00843

Gnomad4 OTH exome

AF:

0.00969

GnomAD4 genome

AF:

0.00620

AC:

944

AN:

152324

Hom.:

Cov.:

AF XY:

0.00589

AC XY:

439

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.00156

Gnomad4 AMR

AF:

0.00935

Gnomad4 ASJ

AF:

0.0259

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0147

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.00804

Gnomad4 OTH

AF:

0.00851

Alfa

AF:

0.00908

Hom.:

Bravo

AF:

0.00671

TwinsUK

AF:

0.00809

AC:

ALSPAC

AF:

0.00986

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00977

AC:

ExAC

AF:

0.00737

AC:

895

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.00845

EpiControl

AF:

0.0100

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 03, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 26, 2015	- -

not provided

Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	HPS6: BP4, BS1, BS2 -

Hermansky-Pudlak syndrome 6

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Benign

0.72

DEOGEN2

Benign

0.12

Eigen

Benign

-0.90

Eigen_PC

Benign

-0.82

FATHMM_MKL

Benign

0.029

LIST_S2

Benign

0.51

MetaRNN

Benign

0.0056

MetaSVM

Benign

-0.99

MutationAssessor

Uncertain

2.3

MutationTaster

Benign

1.0

PrimateAI

Benign

0.30

PROVEAN

Benign

1.0

REVEL

Benign

0.080

Sift

Benign

0.80

Sift4G

Benign

0.31

Polyphen

0.0

Vest4

0.26

MVP

0.57

MPC

0.70

ClinPred

0.0071

GERP RS

2.4

Varity_R

0.060

gMVP

0.27

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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