22-26451986-ACGCGCGCGCGCGCGCG-ACGCGCGCGCGCG

Variant names:

• chr22-26451986-ACGCG-A
• rs10573454
• NM_022081.6:c.*1243_*1246delCGCG

Variant summary

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

The NM_022081.6(HPS4):​c.*1243_*1246delCGCG 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
• 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 (EAS) allele frequency at 95% confidence interval = 0.196 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.*1243_*1246delCGCG		3_prime_UTR	Exon 14 of 14	NP_071364.4
	HPS4	NM_001349900.2		c.*1243_*1246delCGCG		3_prime_UTR	Exon 15 of 15	NP_001336829.1	F1LLU8
	HPS4	NM_001349901.1		c.*1243_*1246delCGCG		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.*1243_*1246delCGCG		3_prime_UTR	Exon 14 of 14	ENSP00000381213.2	Q9NQG7-1
	HPS4	ENST00000422379.3	TSL:5	c.*1243_*1246delCGCG		3_prime_UTR	Exon 15 of 15	ENSP00000415081.3	F1LLU8
	HPS4	ENST00000473782.2	TSL:2	c.*1243_*1246delCGCG		3_prime_UTR	Exon 15 of 15	ENSP00000514223.1	Q9NQG7-1

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

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

African (AFR) AF: 0.0156 AC: 5 AN: 320

American (AMR) AF: 0.0292 AC: 27 AN: 926

Ashkenazi Jewish (ASJ) AF: 0.0673 AC: 21 AN: 312

East Asian (EAS) AF: 0.0625 AC: 19 AN: 304

South Asian (SAS) AF: 0.0378 AC: 91 AN: 2410

European-Finnish (FIN) AF: 0.0522 AC: 24 AN: 460

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 46

European-Non Finnish (NFE) AF: 0.0359 AC: 319 AN: 8894

Other (OTH) AF: 0.0411 AC: 23 AN: 560

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

African (AFR) AF: 0.0866 AC: 2850 AN: 32918

American (AMR) AF: 0.121 AC: 1620 AN: 13432

Ashkenazi Jewish (ASJ) AF: 0.179 AC: 587 AN: 3288

East Asian (EAS) AF: 0.207 AC: 924 AN: 4466

South Asian (SAS) AF: 0.0989 AC: 400 AN: 4046

European-Finnish (FIN) AF: 0.114 AC: 1008 AN: 8804

Middle Eastern (MID) AF: 0.139 AC: 38 AN: 274

European-Non Finnish (NFE) AF: 0.103 AC: 6639 AN: 64346

Other (OTH) AF: 0.126 AC: 236 AN: 1880

Alfa AF: 0.0833 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

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

Other links and lift over

dbSNP: rs10573454; hg19: chr22-26847952;