Genetic Variant HPS4:p.Ile84Val (chr22-26477019-T-C) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -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. 17/22 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:10

Conservation

PhyloP100: -2.99

Publications

10 publications found

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 Gene-Disease associations (from GenCC):

Hermansky-Pudlak syndrome 4
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P, Ambry Genetics
Hermansky-Pudlak syndrome with pulmonary fibrosis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

HPS4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 211153.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022081.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HPS4	NM_022081.6	MANE Select	c.250A>G	p.Ile84Val	missense	Exon 4 of 14	NP_071364.4
HPS4	NM_001349900.2		c.250A>G	p.Ile84Val	missense	Exon 4 of 15	NP_001336829.1	F1LLU8
HPS4	NM_001349901.1		c.250A>G	p.Ile84Val	missense	Exon 4 of 15	NP_001336830.1	F1LLU8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HPS4	ENST00000398145.7	TSL:1 MANE Select	c.250A>G	p.Ile84Val	missense	Exon 4 of 14	ENSP00000381213.2	Q9NQG7-1
HPS4	ENST00000402105.7	TSL:1	c.235A>G	p.Ile79Val	missense	Exon 2 of 12	ENSP00000384185.3	Q9NQG7-3
HPS4	ENST00000439453.5	TSL:1	n.250A>G		non_coding_transcript_exon	Exon 4 of 14	ENSP00000406764.1	F8WC53

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

GnomAD2 exomes

AF:

0.00471

AC:

1184

AN:

251464

AF XY:

0.00508

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 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

African (AFR)

AF:

0.00102

AC:

AN:

33480

American (AMR)

AF:

0.00548

AC:

245

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0139

AC:

364

AN:

26134

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39696

South Asian (SAS)

AF:

0.00576

AC:

497

AN:

86258

European-Finnish (FIN)

AF:

0.000749

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.0522

AC:

301

AN:

5768

European-Non Finnish (NFE)

AF:

0.00380

AC:

4223

AN:

1111980

Other (OTH)

AF:

0.00513

AC:

310

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

335

670

1006

1341

1676

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

154

308

462

616

770

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00343

AC:

522

AN:

152366

Hom.:

Cov.:

AF XY:

0.00361

AC XY:

269

AN XY:

74508

show subpopulations

African (AFR)

AF:

0.000721

AC:

AN:

41586

American (AMR)

AF:

0.00666

AC:

102

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0138

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5190

South Asian (SAS)

AF:

0.00829

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000565

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00394

AC:

268

AN:

68034

Other (OTH)

AF:

0.00851

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

100

125

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00499

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

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

Hermansky-Pudlak syndrome 4 (3)

not provided (3)

Hermansky-Pudlak syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.39

CADD

Benign

0.0010

(source)

DANN

Benign

0.45

DEOGEN2

Benign

0.089

Eigen

Benign

-2.1

Eigen_PC

Benign

-2.2

FATHMM_MKL

Benign

0.032

LIST_S2

Benign

0.54

M_CAP

Benign

0.062

MetaRNN

Benign

0.0055

MetaSVM

Benign

-0.86

MutationAssessor

Benign

-0.26

PhyloP100

-3.0

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.13

REVEL

Benign

0.24

Sift

Benign

0.78

Sift4G

Benign

0.67

Polyphen

0.0030

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

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

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