22-26451986-ACGCGCGCGCGCGCGCG-ACGCGCGCGCG

Variant names:

• chr22-26451986-ACGCGCG-A
• rs10573454
• NM_022081.6:c.*1241_*1246delCGCGCG

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_022081.6(HPS4):​c.*1241_*1246delCGCGCG 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
• 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

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.*1241_*1246delCGCGCG		3_prime_UTR	Exon 14 of 14	NP_071364.4
	HPS4	NM_001349900.2		c.*1241_*1246delCGCGCG		3_prime_UTR	Exon 15 of 15	NP_001336829.1	F1LLU8
	HPS4	NM_001349901.1		c.*1241_*1246delCGCGCG		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.*1241_*1246delCGCGCG		3_prime_UTR	Exon 14 of 14	ENSP00000381213.2	Q9NQG7-1
	HPS4	ENST00000422379.3	TSL:5	c.*1241_*1246delCGCGCG		3_prime_UTR	Exon 15 of 15	ENSP00000415081.3	F1LLU8
	HPS4	ENST00000473782.2	TSL:2	c.*1241_*1246delCGCGCG		3_prime_UTR	Exon 15 of 15	ENSP00000514223.1	Q9NQG7-1

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

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

African (AFR) AF: 0.0255 AC: 8 AN: 314

American (AMR) AF: 0.0502 AC: 47 AN: 936

Ashkenazi Jewish (ASJ) AF: 0.0755 AC: 24 AN: 318

East Asian (EAS) AF: 0.0805 AC: 24 AN: 298

South Asian (SAS) AF: 0.0509 AC: 122 AN: 2396

European-Finnish (FIN) AF: 0.0702 AC: 32 AN: 456

Middle Eastern (MID) AF: 0.0217 AC: 1 AN: 46

European-Non Finnish (NFE) AF: 0.0405 AC: 359 AN: 8868

Other (OTH) AF: 0.0556 AC: 31 AN: 558

⚠️ 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 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

African (AFR) AF: 0.0857 AC: 2822 AN: 32912

American (AMR) AF: 0.103 AC: 1388 AN: 13422

Ashkenazi Jewish (ASJ) AF: 0.123 AC: 405 AN: 3302

East Asian (EAS) AF: 0.175 AC: 784 AN: 4476

South Asian (SAS) AF: 0.118 AC: 478 AN: 4050

European-Finnish (FIN) AF: 0.159 AC: 1391 AN: 8768

Middle Eastern (MID) AF: 0.0985 AC: 27 AN: 274

European-Non Finnish (NFE) AF: 0.0944 AC: 6079 AN: 64408

Other (OTH) AF: 0.100 AC: 188 AN: 1874

Alfa AF: 0.0930 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;