chr22-26451986-ACGCGCGCGCGCG-A

Variant names:

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

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BS1

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. 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

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00378 (54/14304) while in subpopulation MID AF= 0.0217 (1/46). AF 95% confidence interval is 0.00338. There are 0 homozygotes in gnomad4_exome. There are 34 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPS4	NM_022081.6	c.*1235_*1246delCGCGCGCGCGCG		3_prime_UTR_variant	Exon 14 of 14	ENST00000398145.7	NP_071364.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HPS4	ENST00000398145	c.*1235_*1246delCGCGCGCGCGCG		3_prime_UTR_variant	Exon 14 of 14	1	NM_022081.6	ENSP00000381213.2

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

Gnomad4 AFR exome AF: 0.00313

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00955

Gnomad4 EAS exome AF: 0.00327

Gnomad4 SAS exome AF: 0.00290

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00447

Gnomad4 OTH exome AF: 0.00179

GnomAD4 genome AF: 0.0000816 AC: 11 AN: 134840 Hom.: 1 Cov.: 0 AF XY: 0.0000922 AC XY: 6 AN XY: 65098

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000370

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000222

Gnomad4 SAS AF: 0.000246

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000620

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs10573454; hg19: chr22-26847952;