22-26451986-ACG-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_022081.6(HPS4):c.*1245_*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 0.0129 in 149,082 control chromosomes in the GnomAD database, including 19 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.014 (19 hom., cov: 0)
  • Exomes 𝑓: 0.0061 (0 hom.)
• Consequence: HPS4 NM_022081.6 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: -0.477

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 Likely_benign. Variant got -5 ACMG points.

• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0136 (1830/134766) while in subpopulation EAS AF= 0.0209 (94/4504). AF 95% confidence interval is 0.0175. There are 19 homozygotes in gnomad4. There are 871 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HPS4	NM_022081.6	c.*1245_*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.*1245_*1246del		3_prime_UTR_variant	14/14	1	NM_022081.6	P2

Frequencies

GnomAD3 genomes AF: 0.0136 AC: 1829 AN: 134686 Hom.: 19 Cov.: 0

Gnomad AFR AF: 0.0121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0137

Gnomad ASJ AF: 0.0173

Gnomad EAS AF: 0.0206

Gnomad SAS AF: 0.00664

Gnomad FIN AF: 0.0109

Gnomad MID AF: 0.0101

Gnomad NFE AF: 0.0145

Gnomad OTH AF: 0.0182

GnomAD4 exome AF: 0.00608 AC: 87 AN: 14316 Hom.: 0 AF XY: 0.00618 AC XY: 50 AN XY: 8096

Gnomad4 AFR exome AF: 0.0187

Gnomad4 AMR exome AF: 0.00742

Gnomad4 ASJ exome AF: 0.00949

Gnomad4 EAS exome AF: 0.0132

Gnomad4 SAS exome AF: 0.00455

Gnomad4 FIN exome AF: 0.00431

Gnomad4 NFE exome AF: 0.00570

Gnomad4 OTH exome AF: 0.00536

GnomAD4 genome AF: 0.0136 AC: 1830 AN: 134766 Hom.: 19 Cov.: 0 AF XY: 0.0134 AC XY: 871 AN XY: 65068

Gnomad4 AFR AF: 0.0121

Gnomad4 AMR AF: 0.0137

Gnomad4 ASJ AF: 0.0173

Gnomad4 EAS AF: 0.0209

Gnomad4 SAS AF: 0.00665

Gnomad4 FIN AF: 0.0109

Gnomad4 NFE AF: 0.0145

Gnomad4 OTH AF: 0.0181

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Hermansky-Pudlak syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
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;