rs9608491

Variant names:

• chr22-26475019-A-G
• rs9608491
• NM_022081.6:c.276+1974T>C

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 9 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: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Hermansky-Pudlak syndrome with pulmonary fibrosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPS4	NM_022081.6	MANE Select	c.276+1974T>C		intron	N/A	NP_071364.4
	HPS4	NM_001349900.2		c.276+1974T>C		intron	N/A	NP_001336829.1
	HPS4	NM_001349901.1		c.276+1974T>C		intron	N/A	NP_001336830.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPS4	ENST00000398145.7	TSL:1 MANE Select	c.276+1974T>C		intron	N/A	ENSP00000381213.2
	HPS4	ENST00000402105.7	TSL:1	c.261+1974T>C		intron	N/A	ENSP00000384185.3
	HPS4	ENST00000439453.5	TSL:1	n.276+1974T>C		intron	N/A	ENSP00000406764.1

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

African (AFR) AF: 0.135 AC: 5594 AN: 41528

American (AMR) AF: 0.212 AC: 3248 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.226 AC: 785 AN: 3468

East Asian (EAS) AF: 0.120 AC: 619 AN: 5168

South Asian (SAS) AF: 0.182 AC: 876 AN: 4822

European-Finnish (FIN) AF: 0.270 AC: 2864 AN: 10590

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.188 AC: 12792 AN: 67980

Other (OTH) AF: 0.170 AC: 359 AN: 2114

Alfa AF: 0.185 Hom.: 8568

Bravo AF: 0.172

Asia WGS AF: 0.169 AC: 590 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.10
DANN	Benign	0.71
PhyloP100		-0.79
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs9608491; hg19: chr22-26870985;