22-26451986-ACGCGCGCGCGCGCGCG-ACGCGCGCGCGCGCG

Variant names:

• chr22-26451986-ACG-A
• rs10573454
• NM_022081.6:c.*1245_*1246delCG

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_022081.6(HPS4):​c.*1245_*1246delCG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0129 in 149,082 control chromosomes in the GnomAD database, including 19 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (19 hom., cov: 0)
  • Exomes 𝑓: 0.0061 (0 hom.)
• Consequence: HPS4 NM_022081.6 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: -0.477
• 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 -5 ACMG points.

• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0136 (1830/134766) while in subpopulation EAS AF = 0.0209 (94/4504). AF 95% confidence interval is 0.0175. There are 19 homozygotes in GnomAd4. There are 871 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 19 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.*1245_*1246delCG		3_prime_UTR	Exon 14 of 14	NP_071364.4
	HPS4	NM_001349900.2		c.*1245_*1246delCG		3_prime_UTR	Exon 15 of 15	NP_001336829.1	F1LLU8
	HPS4	NM_001349901.1		c.*1245_*1246delCG		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.*1245_*1246delCG		3_prime_UTR	Exon 14 of 14	ENSP00000381213.2	Q9NQG7-1
	HPS4	ENST00000422379.3	TSL:5	c.*1245_*1246delCG		3_prime_UTR	Exon 15 of 15	ENSP00000415081.3	F1LLU8
	HPS4	ENST00000473782.2	TSL:2	c.*1245_*1246delCG		3_prime_UTR	Exon 15 of 15	ENSP00000514223.1	Q9NQG7-1

Frequencies

GnomAD3 genomes AF: 0.0136 AC: 1829 AN: 134686 Hom.: 19 Cov.: 0

Gnomad AFR AF: 0.0121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0137

Gnomad ASJ AF: 0.0173

Gnomad EAS AF: 0.0206

Gnomad SAS AF: 0.00664

Gnomad FIN AF: 0.0109

Gnomad MID AF: 0.0101

Gnomad NFE AF: 0.0145

Gnomad OTH AF: 0.0182

GnomAD4 exome AF: 0.00608 AC: 87 AN: 14316 Hom.: 0 AF XY: 0.00618 AC XY: 50 AN XY: 8096

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

African (AFR) AF: 0.0187 AC: 6 AN: 320

American (AMR) AF: 0.00742 AC: 7 AN: 944

Ashkenazi Jewish (ASJ) AF: 0.00949 AC: 3 AN: 316

East Asian (EAS) AF: 0.0132 AC: 4 AN: 304

South Asian (SAS) AF: 0.00455 AC: 11 AN: 2416

European-Finnish (FIN) AF: 0.00431 AC: 2 AN: 464

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 44

European-Non Finnish (NFE) AF: 0.00570 AC: 51 AN: 8948

Other (OTH) AF: 0.00536 AC: 3 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: 0.0136 AC: 1830 AN: 134766 Hom.: 19 Cov.: 0 AF XY: 0.0134 AC XY: 871 AN XY: 65068

African (AFR) AF: 0.0121 AC: 400 AN: 33050

American (AMR) AF: 0.0137 AC: 185 AN: 13492

Ashkenazi Jewish (ASJ) AF: 0.0173 AC: 57 AN: 3304

East Asian (EAS) AF: 0.0209 AC: 94 AN: 4504

South Asian (SAS) AF: 0.00665 AC: 27 AN: 4062

European-Finnish (FIN) AF: 0.0109 AC: 96 AN: 8836

Middle Eastern (MID) AF: 0.0109 AC: 3 AN: 274

European-Non Finnish (NFE) AF: 0.0145 AC: 934 AN: 64508

Other (OTH) AF: 0.0181 AC: 34 AN: 1882

Alfa AF: 0.00816 Hom.: 273

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Hermansky-Pudlak syndrome (2)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.48
Mutation Taster		=100/0	polymorphism

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;