NM_022081.6:c.*1241_*1246dupCGCGCG

Variant names:

• chr22-26451986-A-ACGCGCG
• rs10573454
• NM_022081.6:c.*1241_*1246dupCGCGCG

Variant summary

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

The NM_022081.6(HPS4):​c.*1241_*1246dupCGCGCG 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 0.000082 (0 hom., cov: 0)
• 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: 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.*1241_*1246dupCGCGCG		3_prime_UTR	Exon 14 of 14	NP_071364.4
	HPS4	NM_001349900.2		c.*1241_*1246dupCGCGCG		3_prime_UTR	Exon 15 of 15	NP_001336829.1	F1LLU8
	HPS4	NM_001349901.1		c.*1241_*1246dupCGCGCG		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.*1241_*1246dupCGCGCG		3_prime_UTR	Exon 14 of 14	ENSP00000381213.2	Q9NQG7-1
	HPS4	ENST00000422379.3	TSL:5	c.*1241_*1246dupCGCGCG		3_prime_UTR	Exon 15 of 15	ENSP00000415081.3	F1LLU8
	HPS4	ENST00000473782.2	TSL:2	c.*1241_*1246dupCGCGCG		3_prime_UTR	Exon 15 of 15	ENSP00000514223.1	Q9NQG7-1

Frequencies

GnomAD3 genomes AF: 0.0000816 AC: 11 AN: 134758 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000742

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000310

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 0

GnomAD4 genome AF: 0.0000816 AC: 11 AN: 134758 Hom.: 0 Cov.: 0 AF XY: 0.0000154 AC XY: 1 AN XY: 65006

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

African (AFR) AF: 0.000242 AC: 8 AN: 32998

American (AMR) AF: 0.0000742 AC: 1 AN: 13484

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 4518

South Asian (SAS) AF: 0.00 AC: 0 AN: 4066

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 298

European-Non Finnish (NFE) AF: 0.0000310 AC: 2 AN: 64536

Other (OTH) AF: 0.00 AC: 0 AN: 1864

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000503110), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 273

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;