22-26451986-ACGCG-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

The NM_022081.6(HPS4):c.*1243_*1246del variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.11 (875 hom., cov: 0)
  • Exomes 𝑓: 0.037 (3 hom.)
  • Failed GnomAD Quality Control
• Consequence: HPS4 NM_022081.6 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.278

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 -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.196 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HPS4	NM_022081.6	c.*1243_*1246del		3_prime_UTR_variant	14/14	ENST00000398145.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HPS4	ENST00000398145.7	c.*1243_*1246del		3_prime_UTR_variant	14/14	1	NM_022081.6	P2

Frequencies

GnomAD3 genomes AF: 0.107 AC: 14380 AN: 134224 Hom.: 875 Cov.: 0

Gnomad AFR AF: 0.0864

Gnomad AMI AF: 0.103

Gnomad AMR AF: 0.121

Gnomad ASJ AF: 0.179

Gnomad EAS AF: 0.207

Gnomad SAS AF: 0.0990

Gnomad FIN AF: 0.114

Gnomad MID AF: 0.128

Gnomad NFE AF: 0.103

Gnomad OTH AF: 0.128

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0372 AC: 529 AN: 14232 Hom.: 3 AF XY: 0.0387 AC XY: 312 AN XY: 8052

Gnomad4 AFR exome AF: 0.0156

Gnomad4 AMR exome AF: 0.0292

Gnomad4 ASJ exome AF: 0.0673

Gnomad4 EAS exome AF: 0.0625

Gnomad4 SAS exome AF: 0.0378

Gnomad4 FIN exome AF: 0.0522

Gnomad4 NFE exome AF: 0.0359

Gnomad4 OTH exome AF: 0.0411

GnomAD4 genome AF: 0.107 AC: 14389 AN: 134302 Hom.: 875 Cov.: 0 AF XY: 0.107 AC XY: 6945 AN XY: 64832

Gnomad4 AFR AF: 0.0866

Gnomad4 AMR AF: 0.121

Gnomad4 ASJ AF: 0.179

Gnomad4 EAS AF: 0.207

Gnomad4 SAS AF: 0.0989

Gnomad4 FIN AF: 0.114

Gnomad4 NFE AF: 0.103

Gnomad4 OTH AF: 0.126

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hermansky-Pudlak syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

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: rs10573454; hg19: chr22-26847952;