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

Variant summary

Our verdict is Benign. Variant got -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

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:

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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 (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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPS4	NM_022081.6 link	c.42-49G>A		intron_variant	Intron 2 of 13	ENST00000398145.7	NP_071364.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HPS4	ENST00000398145.7 link	c.42-49G>A		intron_variant	Intron 2 of 13	1	NM_022081.6	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

GnomAD3 exomes

AF:

0.0633

AC:

14532

AN:

229562

Hom.:

575

AF XY:

0.0630

AC XY:

7828

AN XY:

124276

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 SAS exome

AF:

0.0179

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

Gnomad4 AFR exome

AF:

0.0166

Gnomad4 AMR exome

AF:

0.0413

Gnomad4 ASJ exome

AF:

0.0636

Gnomad4 EAS exome

AF:

0.000178

Gnomad4 SAS exome

AF:

0.0184

Gnomad4 FIN exome

AF:

0.0911

Gnomad4 NFE exome

AF:

0.0892

Gnomad4 OTH exome

AF:

0.0689

GnomAD4 genome

AF:

0.0633

AC:

9631

AN:

152246

Hom.:

433

Cov.:

AF XY:

0.0624

AC XY:

4646

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.0200

Gnomad4 AMR

AF:

0.0621

Gnomad4 ASJ

AF:

0.0712

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0143

Gnomad4 FIN

AF:

0.0924

Gnomad4 NFE

AF:

0.0914

Gnomad4 OTH

AF:

0.0649

Alfa

AF:

0.0824

Hom.:

794

Bravo

AF:

0.0581

Asia WGS

AF:

0.00779

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Nov 12, 2018

GeneDx

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:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

0.38

DANN

Benign

0.76

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