rs2014410

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The NM_022081.6(HPS4):c.1327C>G(p.Leu443Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.398 in 1,613,716 control chromosomes in the GnomAD database, including 130,543 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 0.36 ( 10143 hom., cov: 32)

Exomes 𝑓: 0.40 ( 120400 hom. )

Consequence

HPS4
NM_022081.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.782

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=5.2847725E-5).

BP6

Variant 22-26464303-G-C is Benign according to our data. Variant chr22-26464303-G-C is described in ClinVar as [Benign]. Clinvar id is 163673.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-26464303-G-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.487 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPS4	NM_022081.6 link	c.1327C>G	p.Leu443Val	missense_variant	Exon 11 of 14	ENST00000398145.7	NP_071364.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HPS4	ENST00000398145.7 link	c.1327C>G	p.Leu443Val	missense_variant	Exon 11 of 14	1	NM_022081.6	ENSP00000381213.2		Q9NQG7-1

Frequencies

GnomAD3 genomes

AF:

0.359

AC:

54486

AN:

151876

Hom.:

10130

Cov.:

show subpopulations

Gnomad AFR

AF:

0.308

Gnomad AMI

AF:

0.377

Gnomad AMR

AF:

0.275

Gnomad ASJ

AF:

0.293

Gnomad EAS

AF:

0.298

Gnomad SAS

AF:

0.502

Gnomad FIN

AF:

0.365

Gnomad MID

AF:

0.380

Gnomad NFE

AF:

0.406

Gnomad OTH

AF:

0.342

GnomAD3 exomes

AF:

0.372

AC:

93288

AN:

250926

Hom.:

18400

AF XY:

0.387

AC XY:

52426

AN XY:

135620

show subpopulations

Gnomad AFR exome

AF:

0.312

Gnomad AMR exome

AF:

0.216

Gnomad ASJ exome

AF:

0.319

Gnomad EAS exome

AF:

0.292

Gnomad SAS exome

AF:

0.517

Gnomad FIN exome

AF:

0.364

Gnomad NFE exome

AF:

0.408

Gnomad OTH exome

AF:

0.375

GnomAD4 exome

AF:

0.402

AC:

587687

AN:

1461722

Hom.:

120400

Cov.:

AF XY:

0.407

AC XY:

295635

AN XY:

727152

show subpopulations

Gnomad4 AFR exome

AF:

0.313

Gnomad4 AMR exome

AF:

0.228

Gnomad4 ASJ exome

AF:

0.310

Gnomad4 EAS exome

AF:

0.288

Gnomad4 SAS exome

AF:

0.515

Gnomad4 FIN exome

AF:

0.367

Gnomad4 NFE exome

AF:

0.412

Gnomad4 OTH exome

AF:

0.389

GnomAD4 genome

AF:

0.359

AC:

54527

AN:

151994

Hom.:

10143

Cov.:

AF XY:

0.356

AC XY:

26476

AN XY:

74276

show subpopulations

Gnomad4 AFR

AF:

0.308

Gnomad4 AMR

AF:

0.275

Gnomad4 ASJ

AF:

0.293

Gnomad4 EAS

AF:

0.297

Gnomad4 SAS

AF:

0.503

Gnomad4 FIN

AF:

0.365

Gnomad4 NFE

AF:

0.406

Gnomad4 OTH

AF:

0.347

Alfa

AF:

0.394

Hom.:

9074

Bravo

AF:

0.349

TwinsUK

AF:

0.405

AC:

1502

ALSPAC

AF:

0.412

AC:

1586

ESP6500AA

AF:

0.313

AC:

1381

ESP6500EA

AF:

0.411

AC:

3536

ExAC

AF:

0.383

AC:

46470

Asia WGS

AF:

0.373

AC:

1299

AN:

3478

EpiCase

AF:

0.404

EpiControl

AF:

0.403

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Leu443Val in exon 11 of HPS4: This variant is not expected to have clinical sign ificance because it has been identified in 41.1% (3536/8600) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs2014410). -

Hermansky-Pudlak syndrome 4

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hermansky-Pudlak syndrome

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.56

CADD

Benign

0.079

DANN

Benign

0.45

DEOGEN2

Benign

0.10

T;.;T;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.15

.;T;T;T

MetaRNN

Benign

0.000053

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

L;.;L;.

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.53

N;N;N;N

REVEL

Benign

0.060

Sift

Benign

0.69

T;T;T;T

Sift4G

Benign

0.51

T;T;T;.

Polyphen

0.19

B;B;B;.

Vest4

0.029

MPC

0.049

ClinPred

0.0014

GERP RS

-3.8

Varity_R

0.013

gMVP

0.16

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