chr22-26451986-ACGCGCG-A

Position:

• chr22-26451986-ACGCGCG-A

Variant summary

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

The NM_022081.6(HPS4):​c.*1241_*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 0.0457 in 14,190 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.10 (677 hom., cov: 0)
  • Exomes 𝑓: 0.046 (2 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: GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0555 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HPS4	NM_022081.6	c.*1241_*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.*1241_*1246del		3_prime_UTR_variant	14/14	1	NM_022081.6	ENSP00000381213	P2

Frequencies

GnomAD3 genomes AF: 0.101 AC: 13587 AN: 134264 Hom.: 677 Cov.: 0

Gnomad AFR AF: 0.0858

Gnomad AMI AF: 0.0433

Gnomad AMR AF: 0.103

Gnomad ASJ AF: 0.123

Gnomad EAS AF: 0.175

Gnomad SAS AF: 0.117

Gnomad FIN AF: 0.159

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0944

Gnomad OTH AF: 0.102

GnomAD4 exome AF: 0.0457 AC: 648 AN: 14190 Hom.: 2 AF XY: 0.0473 AC XY: 380 AN XY: 8028

Gnomad4 AFR exome AF: 0.0255

Gnomad4 AMR exome AF: 0.0502

Gnomad4 ASJ exome AF: 0.0755

Gnomad4 EAS exome AF: 0.0805

Gnomad4 SAS exome AF: 0.0509

Gnomad4 FIN exome AF: 0.0702

Gnomad4 NFE exome AF: 0.0405

Gnomad4 OTH exome AF: 0.0556

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.101 AC: 13599 AN: 134340 Hom.: 677 Cov.: 0 AF XY: 0.105 AC XY: 6799 AN XY: 64826

Gnomad4 AFR AF: 0.0857

Gnomad4 AMR AF: 0.103

Gnomad4 ASJ AF: 0.123

Gnomad4 EAS AF: 0.175

Gnomad4 SAS AF: 0.118

Gnomad4 FIN AF: 0.159

Gnomad4 NFE AF: 0.0944

Gnomad4 OTH AF: 0.100

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;