22-26451986-ACGCGCGCGCGCGCGCG-ACGCGCG

Variant names:

• chr22-26451986-ACGCGCGCGCG-A
• rs10573454
• NM_022081.6:c.*1237_*1246delCGCGCGCGCG

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_022081.6(HPS4):​c.*1237_*1246delCGCGCGCGCG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.272 in 14,034 control chromosomes in the GnomAD database, including 526 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.26 (4906 hom., cov: 0)
  • Exomes 𝑓: 0.27 (526 hom.)
  • Failed GnomAD Quality Control
• Consequence: HPS4 NM_022081.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B: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 -10 ACMG points.

• BP6: Variant 22-26451986-ACGCGCGCGCG-A is Benign according to our data. Variant chr22-26451986-ACGCGCGCGCG-A is described in ClinVar as Benign. ClinVar VariationId is 340976.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.278 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.*1237_*1246delCGCGCGCGCG		3_prime_UTR	Exon 14 of 14	NP_071364.4
	HPS4	NM_001349900.2		c.*1237_*1246delCGCGCGCGCG		3_prime_UTR	Exon 15 of 15	NP_001336829.1	F1LLU8
	HPS4	NM_001349901.1		c.*1237_*1246delCGCGCGCGCG		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.*1237_*1246delCGCGCGCGCG		3_prime_UTR	Exon 14 of 14	ENSP00000381213.2	Q9NQG7-1
	HPS4	ENST00000422379.3	TSL:5	c.*1237_*1246delCGCGCGCGCG		3_prime_UTR	Exon 15 of 15	ENSP00000415081.3	F1LLU8
	HPS4	ENST00000473782.2	TSL:2	c.*1237_*1246delCGCGCGCGCG		3_prime_UTR	Exon 15 of 15	ENSP00000514223.1	Q9NQG7-1

Frequencies

GnomAD3 genomes AF: 0.259 AC: 34753 AN: 134394 Hom.: 4907 Cov.: 0

Gnomad AFR AF: 0.125

Gnomad AMI AF: 0.404

Gnomad AMR AF: 0.212

Gnomad ASJ AF: 0.352

Gnomad EAS AF: 0.213

Gnomad SAS AF: 0.302

Gnomad FIN AF: 0.324

Gnomad MID AF: 0.252

Gnomad NFE AF: 0.321

Gnomad OTH AF: 0.259

GnomAD4 exome AF: 0.272 AC: 3822 AN: 14034 Hom.: 526 AF XY: 0.276 AC XY: 2188 AN XY: 7930

African (AFR) AF: 0.127 AC: 40 AN: 314

American (AMR) AF: 0.169 AC: 156 AN: 922

Ashkenazi Jewish (ASJ) AF: 0.285 AC: 89 AN: 312

East Asian (EAS) AF: 0.193 AC: 57 AN: 296

South Asian (SAS) AF: 0.288 AC: 681 AN: 2364

European-Finnish (FIN) AF: 0.270 AC: 123 AN: 456

Middle Eastern (MID) AF: 0.326 AC: 15 AN: 46

European-Non Finnish (NFE) AF: 0.288 AC: 2526 AN: 8778

Other (OTH) AF: 0.247 AC: 135 AN: 546

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.258 AC: 34760 AN: 134474 Hom.: 4906 Cov.: 0 AF XY: 0.257 AC XY: 16706 AN XY: 64928

African (AFR) AF: 0.125 AC: 4131 AN: 32992

American (AMR) AF: 0.212 AC: 2858 AN: 13476

Ashkenazi Jewish (ASJ) AF: 0.352 AC: 1158 AN: 3292

East Asian (EAS) AF: 0.213 AC: 958 AN: 4502

South Asian (SAS) AF: 0.304 AC: 1229 AN: 4046

European-Finnish (FIN) AF: 0.324 AC: 2851 AN: 8804

Middle Eastern (MID) AF: 0.246 AC: 68 AN: 276

European-Non Finnish (NFE) AF: 0.321 AC: 20674 AN: 64358

Other (OTH) AF: 0.261 AC: 490 AN: 1878

Alfa AF: 0.248 Hom.: 273

ClinVar

ClinVar submissions

Significance: Benign

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; COSMIC: COSV105212185; COSMIC: COSV105212185;