rs739289

Positions:

• chr22-26466187-C-A
• chr22-26466187-C-G
• chr22-26466187-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_022081.6(HPS4):​c.706+39G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.871 in 1,613,106 control chromosomes in the GnomAD database, including 616,054 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.82 (51970 hom., cov: 32)
  • Exomes 𝑓: 0.88 (564084 hom.)
• Consequence: HPS4 NM_022081.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -4.09

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 22-26466187-C-A is Benign according to our data. Variant chr22-26466187-C-A is described in ClinVar as [Benign]. Clinvar id is 261537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.887 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HPS4	NM_022081.6	c.706+39G>T		intron_variant		ENST00000398145.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HPS4	ENST00000398145.7	c.706+39G>T		intron_variant		1	NM_022081.6	P2

Frequencies

GnomAD3 genomes AF: 0.821 AC: 124842 AN: 152054 Hom.: 51963 Cov.: 32

Gnomad AFR AF: 0.687

Gnomad AMI AF: 0.832

Gnomad AMR AF: 0.744

Gnomad ASJ AF: 0.865

Gnomad EAS AF: 0.786

Gnomad SAS AF: 0.892

Gnomad FIN AF: 0.958

Gnomad MID AF: 0.883

Gnomad NFE AF: 0.893

Gnomad OTH AF: 0.834

GnomAD3 exomes AF: 0.844 AC: 212227 AN: 251384 Hom.: 90823 AF XY: 0.857 AC XY: 116503 AN XY: 135882

Gnomad AFR exome AF: 0.683

Gnomad AMR exome AF: 0.661

Gnomad ASJ exome AF: 0.867

Gnomad EAS exome AF: 0.792

Gnomad SAS exome AF: 0.900

Gnomad FIN exome AF: 0.957

Gnomad NFE exome AF: 0.892

Gnomad OTH exome AF: 0.867

GnomAD4 exome AF: 0.877 AC: 1280845 AN: 1460934 Hom.: 564084 Cov.: 37 AF XY: 0.880 AC XY: 639402 AN XY: 726830

Gnomad4 AFR exome AF: 0.680

Gnomad4 AMR exome AF: 0.676

Gnomad4 ASJ exome AF: 0.863

Gnomad4 EAS exome AF: 0.768

Gnomad4 SAS exome AF: 0.905

Gnomad4 FIN exome AF: 0.950

Gnomad4 NFE exome AF: 0.890

Gnomad4 OTH exome AF: 0.869

GnomAD4 genome AF: 0.821 AC: 124898 AN: 152172 Hom.: 51970 Cov.: 32 AF XY: 0.822 AC XY: 61187 AN XY: 74412

Gnomad4 AFR AF: 0.686

Gnomad4 AMR AF: 0.744

Gnomad4 ASJ AF: 0.865

Gnomad4 EAS AF: 0.786

Gnomad4 SAS AF: 0.892

Gnomad4 FIN AF: 0.958

Gnomad4 NFE AF: 0.893

Gnomad4 OTH AF: 0.831

Alfa AF: 0.869 Hom.: 54702

Bravo AF: 0.796

Asia WGS AF: 0.809 AC: 2815 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

- -

Hermansky-Pudlak syndrome 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.027
DANN	Benign	0.62
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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

Other links and lift over

dbSNP: rs739289; hg19: chr22-26862153; COSMIC: COSV61102900; COSMIC: COSV61102900;