22-26466246-T-C

Position:

chr22-26466246-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_022081.6(HPS4):c.686A>G(p.Glu229Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.871 in 1,613,862 control chromosomes in the GnomAD database, including 616,234 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 Benign (★★).

Frequency

Genomes: 𝑓 0.82 ( 51959 hom., cov: 32)

Exomes 𝑓: 0.88 ( 564275 hom. )

Consequence

HPS4
NM_022081.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.170

Variant links:

Genes affected

HPS4 (HGNC:15844): (HPS4 biogenesis of lysosomal organelles complex 3 subunit 2) This gene encodes a protein component of biogenesis of lysosome-related organelles complexes (BLOC). BLOC complexes are important for the formation of endosomal-lysosomal organelles such as melanosomes and platelet dense granules. Mutations in this gene result in subtype 4 of Hermansky-Pudlak syndrome, a form of albinism. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2012]

HPS4 links:

HPS4 (HGNC:):

HPS4 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=8.188877E-7).

BP6

Variant 22-26466246-T-C is Benign according to our data. Variant chr22-26466246-T-C is described in ClinVar as [Benign]. Clinvar id is 163674.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-26466246-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.887 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HPS4	NM_022081.6 linkuse as main transcript	c.686A>G	p.Glu229Gly	missense_variant	9/14	ENST00000398145.7	NP_071364.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HPS4	ENST00000398145.7 linkuse as main transcript	c.686A>G	p.Glu229Gly	missense_variant	9/14	1	NM_022081.6	ENSP00000381213.2		Q9NQG7-1

Frequencies

GnomAD3 genomes

AF:

0.821

AC:

124833

AN:

152074

Hom.:

51952

Cov.:

show subpopulations

Gnomad AFR

AF:

0.686

Gnomad AMI

AF:

0.832

Gnomad AMR

AF:

0.744

Gnomad ASJ

AF:

0.865

Gnomad EAS

AF:

0.786

Gnomad SAS

AF:

0.892

Gnomad FIN

AF:

0.958

Gnomad MID

AF:

0.883

Gnomad NFE

AF:

0.893

Gnomad OTH

AF:

0.833

GnomAD3 exomes

AF:

0.844

AC:

212237

AN:

251394

Hom.:

90824

AF XY:

0.857

AC XY:

116494

AN XY:

135876

show subpopulations

Gnomad AFR exome

AF:

0.683

Gnomad AMR exome

AF:

0.661

Gnomad ASJ exome

AF:

0.867

Gnomad EAS exome

AF:

0.792

Gnomad SAS exome

AF:

0.900

Gnomad FIN exome

AF:

0.957

Gnomad NFE exome

AF:

0.892

Gnomad OTH exome

AF:

0.867

GnomAD4 exome

AF:

0.877

AC:

1281410

AN:

1461670

Hom.:

564275

Cov.:

AF XY:

0.880

AC XY:

639631

AN XY:

727146

show subpopulations

Gnomad4 AFR exome

AF:

0.681

Gnomad4 AMR exome

AF:

0.676

Gnomad4 ASJ exome

AF:

0.863

Gnomad4 EAS exome

AF:

0.768

Gnomad4 SAS exome

AF:

0.905

Gnomad4 FIN exome

AF:

0.950

Gnomad4 NFE exome

AF:

0.889

Gnomad4 OTH exome

AF:

0.869

GnomAD4 genome

AF:

0.821

AC:

124889

AN:

152192

Hom.:

51959

Cov.:

AF XY:

0.822

AC XY:

61178

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.686

Gnomad4 AMR

AF:

0.743

Gnomad4 ASJ

AF:

0.865

Gnomad4 EAS

AF:

0.786

Gnomad4 SAS

AF:

0.892

Gnomad4 FIN

AF:

0.958

Gnomad4 NFE

AF:

0.893

Gnomad4 OTH

AF:

0.830

Alfa

AF:

0.875

Hom.:

140965

Bravo

AF:

0.796

TwinsUK

AF:

0.883

AC:

3276

ALSPAC

AF:

0.882

AC:

3400

ESP6500AA

AF:

0.689

AC:

3034

ESP6500EA

AF:

0.888

AC:

7638

ExAC

AF:

0.849

AC:

103023

Asia WGS

AF:

0.809

AC:

2814

AN:

3478

EpiCase

AF:

0.895

EpiControl

AF:

0.888

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Glu229Gly in exon 9 of HPS4: This variant is not expected to have clinical signi ficance because it has been identified in 31.1% (1372/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs713998). -

Hermansky-Pudlak syndrome 4

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Hermansky-Pudlak syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.042

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Benign

0.62

DEOGEN2

Benign

0.079

T;.;T;.

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.0029

LIST_S2

Benign

0.17

.;T;T;T

MetaRNN

Benign

8.2e-7

T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-1.9

N;.;N;.

PrimateAI

Benign

0.31

PROVEAN

Benign

1.7

N;N;N;N

REVEL

Uncertain

0.33

Sift

Benign

0.65

T;T;T;T

Sift4G

Benign

0.47

T;T;T;.

Polyphen

0.0

B;B;B;.

Vest4

0.023

MPC

0.049

ClinPred

0.0022

GERP RS

0.46

Varity_R

0.023

gMVP

0.36

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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