Genetic Variant HPS4:c.-23G>A (chr22-26479404-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_152841.2(HPS4):c.-23G>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0768 in 1,603,012 control chromosomes in the GnomAD database, including 5,236 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.063 ( 433 hom., cov: 32)

Exomes 𝑓: 0.078 ( 4803 hom. )

Consequence

HPS4
NM_152841.2 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -1.62

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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.77).

BP6

Variant 22-26479404-C-T is Benign according to our data. Variant chr22-26479404-C-T is described in ClinVar as Benign. ClinVar VariationId is 261536.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0895 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152841.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HPS4	NM_022081.6	MANE Select	c.42-49G>A	intron	N/A	NP_071364.4
HPS4	NM_152841.2		c.-23G>A	5_prime_UTR_premature_start_codon_gain	Exon 1 of 12	NP_690054.1	Q9NQG7-3
HPS4	NM_152841.2		c.-23G>A	5_prime_UTR	Exon 1 of 12	NP_690054.1	Q9NQG7-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HPS4	ENST00000402105.7	TSL:1	c.-23G>A	5_prime_UTR_premature_start_codon_gain	Exon 1 of 12	ENSP00000384185.3	Q9NQG7-3
HPS4	ENST00000402105.7	TSL:1	c.-23G>A	5_prime_UTR	Exon 1 of 12	ENSP00000384185.3	Q9NQG7-3
HPS4	ENST00000398145.7	TSL:1 MANE Select	c.42-49G>A	intron	N/A	ENSP00000381213.2	Q9NQG7-1

Frequencies

GnomAD3 genomes

AF:

0.0633

AC:

9636

AN:

152130

Hom.:

433

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0201

Gnomad AMI

AF:

0.205

Gnomad AMR

AF:

0.0621

Gnomad ASJ

AF:

0.0712

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0145

Gnomad FIN

AF:

0.0924

Gnomad MID

AF:

0.0538

Gnomad NFE

AF:

0.0914

Gnomad OTH

AF:

0.0656

GnomAD2 exomes

AF:

0.0633

AC:

14532

AN:

229562

AF XY:

0.0630

show subpopulations

Gnomad AFR exome

AF:

0.0204

Gnomad AMR exome

AF:

0.0411

Gnomad ASJ exome

AF:

0.0601

Gnomad EAS exome

AF:

0.000239

Gnomad FIN exome

AF:

0.0965

Gnomad NFE exome

AF:

0.0930

Gnomad OTH exome

AF:

0.0711

GnomAD4 exome

AF:

0.0782

AC:

113459

AN:

1450766

Hom.:

4803

Cov.:

AF XY:

0.0770

AC XY:

55499

AN XY:

720962

show subpopulations

African (AFR)

AF:

0.0166

AC:

546

AN:

32968

American (AMR)

AF:

0.0413

AC:

1788

AN:

43306

Ashkenazi Jewish (ASJ)

AF:

0.0636

AC:

1650

AN:

25940

East Asian (EAS)

AF:

0.000178

AC:

AN:

39250

South Asian (SAS)

AF:

0.0184

AC:

1565

AN:

84842

European-Finnish (FIN)

AF:

0.0911

AC:

4817

AN:

52862

Middle Eastern (MID)

AF:

0.0461

AC:

265

AN:

5754

European-Non Finnish (NFE)

AF:

0.0892

AC:

98696

AN:

1105944

Other (OTH)

AF:

0.0689

AC:

4125

AN:

59900

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

5218

10436

15655

20873

26091

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3494

6988

10482

13976

17470

<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:

0.0633

AC:

9631

AN:

152246

Hom.:

433

Cov.:

AF XY:

0.0624

AC XY:

4646

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.0200

AC:

833

AN:

41562

American (AMR)

AF:

0.0621

AC:

949

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0712

AC:

247

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5188

South Asian (SAS)

AF:

0.0143

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0924

AC:

979

AN:

10592

Middle Eastern (MID)

AF:

0.0510

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0914

AC:

6214

AN:

68006

Other (OTH)

AF:

0.0649

AC:

137

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

459

918

1378

1837

2296

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

224

336

448

560

<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:

0.0806

Hom.:

972

Bravo

AF:

0.0581

Asia WGS

AF:

0.00779

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

0.38

(source)

DANN

Benign

0.76

PhyloP100

-1.6

PromoterAI

-0.081

Neutral

(source)

Mutation Taster

=300/0

polymorphism (auto)

(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

Other links and lift over