22-26477019-T-C

Position:

chr22-26477019-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_022081.6(HPS4):c.250A>G(p.Ile84Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00405 in 1,614,220 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I84L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0034 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0041 ( 35 hom. )

Consequence

HPS4
NM_022081.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:8

Conservation

PhyloP100: -2.99

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005489439).

BP6

Variant 22-26477019-T-C is Benign according to our data. Variant chr22-26477019-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 211153.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=2, Benign=2}. Variant chr22-26477019-T-C is described in Lovd as [Benign]. Variant chr22-26477019-T-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00343 (522/152366) while in subpopulation SAS AF= 0.00828 (40/4828). AF 95% confidence interval is 0.00625. There are 3 homozygotes in gnomad4. There are 269 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HPS4	NM_022081.6 linkuse as main transcript	c.250A>G	p.Ile84Val	missense_variant	4/14	ENST00000398145.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HPS4	ENST00000398145.7 linkuse as main transcript	c.250A>G	p.Ile84Val	missense_variant	4/14	1	NM_022081.6	P2	Q9NQG7-1

Frequencies

GnomAD3 genomes

AF:

0.00343

AC:

522

AN:

152248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00667

Gnomad ASJ

AF:

0.0138

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00828

Gnomad FIN

AF:

0.000565

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.00394

Gnomad OTH

AF:

0.00812

GnomAD3 exomes

AF:

0.00471

AC:

1184

AN:

251464

Hom.:

AF XY:

0.00508

AC XY:

691

AN XY:

135900

show subpopulations

Gnomad AFR exome

AF:

0.000677

Gnomad AMR exome

AF:

0.00544

Gnomad ASJ exome

AF:

0.0138

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00559

Gnomad FIN exome

AF:

0.000462

Gnomad NFE exome

AF:

0.00518

Gnomad OTH exome

AF:

0.0124

GnomAD4 exome

AF:

0.00412

AC:

6016

AN:

1461854

Hom.:

Cov.:

AF XY:

0.00436

AC XY:

3170

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.00102

Gnomad4 AMR exome

AF:

0.00548

Gnomad4 ASJ exome

AF:

0.0139

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00576

Gnomad4 FIN exome

AF:

0.000749

Gnomad4 NFE exome

AF:

0.00380

Gnomad4 OTH exome

AF:

0.00513

GnomAD4 genome

AF:

0.00343

AC:

522

AN:

152366

Hom.:

Cov.:

AF XY:

0.00361

AC XY:

269

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.000721

Gnomad4 AMR

AF:

0.00666

Gnomad4 ASJ

AF:

0.0138

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00829

Gnomad4 FIN

AF:

0.000565

Gnomad4 NFE

AF:

0.00394

Gnomad4 OTH

AF:

0.00851

Alfa

AF:

0.00531

Hom.:

Bravo

AF:

0.00393

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00430

AC:

ExAC

AF:

0.00465

AC:

565

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00578

EpiControl

AF:

0.00688

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 09, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 07, 2016	p.Ile84Val in exon 4 of HPS4: This variant is not expected to have clinical sign ificance because it has been identified in 0.6% (400/66734) of European chromoso mes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; d bSNP rs149830675). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 12, 2016	- -

Hermansky-Pudlak syndrome 4

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Jun 22, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Mar 29, 2021	- -

not provided

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Hermansky-Pudlak syndrome

Uncertain:1

Uncertain significance, 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

0.065

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.39

CADD

Benign

0.0010

DANN

Benign

0.45

DEOGEN2

Benign

0.089

T;.;T;.

Eigen

Benign

-2.1

Eigen_PC

Benign

-2.2

FATHMM_MKL

Benign

0.032

M_CAP

Benign

0.062

MetaRNN

Benign

0.0055

T;T;T;T

MetaSVM

Benign

-0.86

MutationAssessor

Benign

-0.26

N;.;N;.

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.13

N;N;N;N

REVEL

Benign

0.24

Sift

Benign

0.78

T;T;T;T

Sift4G

Benign

0.67

T;T;T;.

Polyphen

0.0030

B;B;B;.

Vest4

0.14

MVP

0.35

MPC

0.042

ClinPred

0.0012

GERP RS

-11

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.017

gMVP

0.25

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