22-26451986-ACGCGCGCG-A

Variant names:

• chr22-26451986-ACGCGCGCG-A
• rs10573454
• NM_022081.6:c.*1239_*1246delCGCGCGCG

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_022081.6(HPS4):​c.*1239_*1246delCGCGCGCG 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
• Publications: 1 publications found

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]

HPS4 Gene-Disease associations (from GenCC):

• Hermansky-Pudlak syndrome 4

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P, Ambry Genetics
• Hermansky-Pudlak syndrome with pulmonary fibrosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.156 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022081.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPS4	NM_022081.6	MANE Select	c.*1239_*1246delCGCGCGCG		3_prime_UTR	Exon 14 of 14	NP_071364.4
	HPS4	NM_001349900.2		c.*1239_*1246delCGCGCGCG		3_prime_UTR	Exon 15 of 15	NP_001336829.1	F1LLU8
	HPS4	NM_001349901.1		c.*1239_*1246delCGCGCGCG		3_prime_UTR	Exon 15 of 15	NP_001336830.1	F1LLU8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPS4	ENST00000398145.7	TSL:1 MANE Select	c.*1239_*1246delCGCGCGCG		3_prime_UTR	Exon 14 of 14	ENSP00000381213.2	Q9NQG7-1
	HPS4	ENST00000422379.3	TSL:5	c.*1239_*1246delCGCGCGCG		3_prime_UTR	Exon 15 of 15	ENSP00000415081.3	F1LLU8
	HPS4	ENST00000473782.2	TSL:2	c.*1239_*1246delCGCGCGCG		3_prime_UTR	Exon 15 of 15	ENSP00000514223.1	Q9NQG7-1

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0541 AC: 17 AN: 314

American (AMR) AF: 0.0648 AC: 60 AN: 926

Ashkenazi Jewish (ASJ) AF: 0.0506 AC: 16 AN: 316

East Asian (EAS) AF: 0.101 AC: 30 AN: 296

South Asian (SAS) AF: 0.0945 AC: 225 AN: 2380

European-Finnish (FIN) AF: 0.0917 AC: 42 AN: 458

Middle Eastern (MID) AF: 0.136 AC: 6 AN: 44

European-Non Finnish (NFE) AF: 0.0886 AC: 783 AN: 8838

Other (OTH) AF: 0.0776 AC: 43 AN: 554

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

African (AFR) AF: 0.160 AC: 5251 AN: 32868

American (AMR) AF: 0.134 AC: 1803 AN: 13434

Ashkenazi Jewish (ASJ) AF: 0.0682 AC: 225 AN: 3298

East Asian (EAS) AF: 0.0906 AC: 407 AN: 4492

South Asian (SAS) AF: 0.162 AC: 656 AN: 4052

European-Finnish (FIN) AF: 0.117 AC: 1025 AN: 8794

Middle Eastern (MID) AF: 0.0833 AC: 23 AN: 276

European-Non Finnish (NFE) AF: 0.145 AC: 9337 AN: 64334

Other (OTH) AF: 0.133 AC: 249 AN: 1878

Alfa AF: 0.0957 Hom.: 273

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Hermansky-Pudlak syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.28
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs10573454; hg19: chr22-26847952;