chr22-26451986-ACGCGCGCGCGCG-A

Variant names:

• chr22-26451986-ACGCGCGCGCGCG-A
• rs10573454
• NM_022081.6:c.*1235_*1246delCGCGCGCGCGCG

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_022081.6(HPS4):​c.*1235_*1246delCGCGCGCGCGCG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000436 in 149,144 control chromosomes in the GnomAD database, including 1 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000082 (1 hom., cov: 0)
  • Exomes 𝑓: 0.0038 (0 hom.)
• Consequence: HPS4 NM_022081.6 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 0 ACMG points.

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.*1235_*1246delCGCGCGCGCGCG		3_prime_UTR	Exon 14 of 14	NP_071364.4
	HPS4	NM_001349900.2		c.*1235_*1246delCGCGCGCGCGCG		3_prime_UTR	Exon 15 of 15	NP_001336829.1	F1LLU8
	HPS4	NM_001349901.1		c.*1235_*1246delCGCGCGCGCGCG		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.*1235_*1246delCGCGCGCGCGCG		3_prime_UTR	Exon 14 of 14	ENSP00000381213.2	Q9NQG7-1
	HPS4	ENST00000422379.3	TSL:5	c.*1235_*1246delCGCGCGCGCGCG		3_prime_UTR	Exon 15 of 15	ENSP00000415081.3	F1LLU8
	HPS4	ENST00000473782.2	TSL:2	c.*1235_*1246delCGCGCGCGCGCG		3_prime_UTR	Exon 15 of 15	ENSP00000514223.1	Q9NQG7-1

Frequencies

GnomAD3 genomes AF: 0.0000816 AC: 11 AN: 134760 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000371

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000221

Gnomad SAS AF: 0.000246

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000620

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00378 AC: 54 AN: 14304 Hom.: 0 AF XY: 0.00420 AC XY: 34 AN XY: 8096

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

African (AFR) AF: 0.00313 AC: 1 AN: 320

American (AMR) AF: 0.00 AC: 0 AN: 942

Ashkenazi Jewish (ASJ) AF: 0.00955 AC: 3 AN: 314

East Asian (EAS) AF: 0.00327 AC: 1 AN: 306

South Asian (SAS) AF: 0.00290 AC: 7 AN: 2412

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 462

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

European-Non Finnish (NFE) AF: 0.00447 AC: 40 AN: 8942

Other (OTH) AF: 0.00179 AC: 1 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: 0.0000816 AC: 11 AN: 134840 Hom.: 1 Cov.: 0 AF XY: 0.0000922 AC XY: 6 AN XY: 65098

African (AFR) AF: 0.00 AC: 0 AN: 33082

American (AMR) AF: 0.000370 AC: 5 AN: 13504

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

East Asian (EAS) AF: 0.000222 AC: 1 AN: 4510

South Asian (SAS) AF: 0.000246 AC: 1 AN: 4062

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 276

European-Non Finnish (NFE) AF: 0.0000620 AC: 4 AN: 64530

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

Alfa AF: 0.00 Hom.: 273

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.28

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;