chr22-26451986-ACGCGCGCG-A

Position:

• chr22-26451986-ACGCGCGCG-A

Variant summary

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

The NM_022081.6(HPS4):​c.*1239_*1246del variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.137 in 148,410 control chromosomes in the GnomAD database, including 1,380 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.14 (1366 hom., cov: 0)
  • Exomes 𝑓: 0.087 (14 hom.)
• 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 (SAS) allele frequency at 95% confidence interval = 0.156 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HPS4	NM_022081.6	c.*1239_*1246del		3_prime_UTR_variant	14/14	ENST00000398145.7	NP_071364.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HPS4	ENST00000398145.7	c.*1239_*1246del		3_prime_UTR_variant	14/14	1	NM_022081.6	ENSP00000381213	P2

Frequencies

GnomAD3 genomes AF: 0.143 AC: 19151 AN: 134208 Hom.: 1368 Cov.: 0

Gnomad AFR AF: 0.160

Gnomad AMI AF: 0.190

Gnomad AMR AF: 0.135

Gnomad ASJ AF: 0.0682

Gnomad EAS AF: 0.0909

Gnomad SAS AF: 0.163

Gnomad FIN AF: 0.117

Gnomad MID AF: 0.0940

Gnomad NFE AF: 0.145

Gnomad OTH AF: 0.134

GnomAD4 exome AF: 0.0865 AC: 1222 AN: 14126 Hom.: 14 AF XY: 0.0862 AC XY: 688 AN XY: 7982

Gnomad4 AFR exome AF: 0.0541

Gnomad4 AMR exome AF: 0.0648

Gnomad4 ASJ exome AF: 0.0506

Gnomad4 EAS exome AF: 0.101

Gnomad4 SAS exome AF: 0.0945

Gnomad4 FIN exome AF: 0.0917

Gnomad4 NFE exome AF: 0.0886

Gnomad4 OTH exome AF: 0.0776

GnomAD4 genome AF: 0.143 AC: 19139 AN: 134284 Hom.: 1366 Cov.: 0 AF XY: 0.142 AC XY: 9187 AN XY: 64842

Gnomad4 AFR AF: 0.160

Gnomad4 AMR AF: 0.134

Gnomad4 ASJ AF: 0.0682

Gnomad4 EAS AF: 0.0906

Gnomad4 SAS AF: 0.162

Gnomad4 FIN AF: 0.117

Gnomad4 NFE AF: 0.145

Gnomad4 OTH AF: 0.133

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

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;