22-26451986-ACGCGCGCGCGCGCGCG-ACGCGCGCGCGCGCGCGCG

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

The NM_022081.6(HPS4):​c.*1245_*1246dupCG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00028 (0 hom.)
• Consequence: HPS4 NM_022081.6 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• 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 -4 ACMG points.

• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000304 (41/134834) while in subpopulation SAS AF = 0.000985 (4/4062). AF 95% confidence interval is 0.000576. There are 0 homozygotes in GnomAd4. There are 20 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

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_*1246dupCG		3_prime_UTR	Exon 14 of 14	NP_071364.4
	HPS4	NM_001349900.2		c.*1245_*1246dupCG		3_prime_UTR	Exon 15 of 15	NP_001336829.1	F1LLU8
	HPS4	NM_001349901.1		c.*1245_*1246dupCG		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_*1246dupCG		3_prime_UTR	Exon 14 of 14	ENSP00000381213.2	Q9NQG7-1
	HPS4	ENST00000422379.3	TSL:5	c.*1245_*1246dupCG		3_prime_UTR	Exon 15 of 15	ENSP00000415081.3	F1LLU8
	HPS4	ENST00000473782.2	TSL:2	c.*1245_*1246dupCG		3_prime_UTR	Exon 15 of 15	ENSP00000514223.1	Q9NQG7-1

Frequencies

GnomAD3 genomes AF: 0.000304 AC: 41 AN: 134754 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000818

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000148

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000664

Gnomad SAS AF: 0.000984

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000775

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000279 AC: 4 AN: 14342 Hom.: 0 Cov.: 0 AF XY: 0.000370 AC XY: 3 AN XY: 8110

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

African (AFR) AF: 0.00 AC: 0 AN: 320

American (AMR) AF: 0.00 AC: 0 AN: 946

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 318

East Asian (EAS) AF: 0.00 AC: 0 AN: 306

South Asian (SAS) AF: 0.00166 AC: 4 AN: 2416

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 464

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 8964

Other (OTH) AF: 0.00 AC: 0 AN: 562

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00955443), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000304 AC: 41 AN: 134834 Hom.: 0 Cov.: 0 AF XY: 0.000307 AC XY: 20 AN XY: 65094

African (AFR) AF: 0.000816 AC: 27 AN: 33078

American (AMR) AF: 0.000148 AC: 2 AN: 13504

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3304

East Asian (EAS) AF: 0.000665 AC: 3 AN: 4510

South Asian (SAS) AF: 0.000985 AC: 4 AN: 4062

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8836

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 274

European-Non Finnish (NFE) AF: 0.0000775 AC: 5 AN: 64530

Other (OTH) AF: 0.00 AC: 0 AN: 1882

Alfa AF: 0.00 Hom.: 273

Bravo AF: 0.000268

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.48

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;