rs9608491

Positions:

• chr22-26475019-A-G
• chr22-26475019-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_022081.6(HPS4):​c.276+1974T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.18 in 152,166 control chromosomes in the GnomAD database, including 2,651 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.18 (2651 hom., cov: 33)
• Consequence: HPS4 NM_022081.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.791

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.206 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HPS4	NM_022081.6	c.276+1974T>C		intron_variant		ENST00000398145.7	NP_071364.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HPS4	ENST00000398145.7	c.276+1974T>C		intron_variant		1	NM_022081.6	ENSP00000381213.2

Frequencies

GnomAD3 genomes AF: 0.180 AC: 27418 AN: 152048 Hom.: 2652 Cov.: 33

Gnomad AFR AF: 0.135

Gnomad AMI AF: 0.266

Gnomad AMR AF: 0.213

Gnomad ASJ AF: 0.226

Gnomad EAS AF: 0.120

Gnomad SAS AF: 0.183

Gnomad FIN AF: 0.270

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.188

Gnomad OTH AF: 0.172

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.180 AC: 27412 AN: 152166 Hom.: 2651 Cov.: 33 AF XY: 0.184 AC XY: 13663 AN XY: 74410

Gnomad4 AFR AF: 0.135

Gnomad4 AMR AF: 0.212

Gnomad4 ASJ AF: 0.226

Gnomad4 EAS AF: 0.120

Gnomad4 SAS AF: 0.182

Gnomad4 FIN AF: 0.270

Gnomad4 NFE AF: 0.188

Gnomad4 OTH AF: 0.170

Alfa AF: 0.187 Hom.: 3647

Bravo AF: 0.172

Asia WGS AF: 0.169 AC: 590 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.10
DANN	Benign	0.71

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

Publications

LitVar

Other links and lift over

dbSNP: rs9608491; hg19: chr22-26870985;