22-26472524-C-T

Variant names:

• chr22-26472524-C-T
• rs17401652
• NM_022081.6:c.385-106G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_022081.6(HPS4):​c.385-106G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0734 in 838,652 control chromosomes in the GnomAD database, including 2,717 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.073 (471 hom., cov: 33)
  • Exomes 𝑓: 0.074 (2246 hom.)
• Consequence: HPS4 NM_022081.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.51
• Publications: 2 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 22-26472524-C-T is Benign according to our data. Variant chr22-26472524-C-T is described in ClinVar as Benign. ClinVar VariationId is 1228330.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0926 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.385-106G>A		intron	N/A	NP_071364.4
	HPS4	NM_001349900.2		c.385-106G>A		intron	N/A	NP_001336829.1
	HPS4	NM_001349901.1		c.385-106G>A		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.385-106G>A		intron	N/A	ENSP00000381213.2
	HPS4	ENST00000402105.7	TSL:1	c.370-106G>A		intron	N/A	ENSP00000384185.3
	HPS4	ENST00000439453.5	TSL:1	n.385-106G>A		intron	N/A	ENSP00000406764.1

Frequencies

GnomAD3 genomes AF: 0.0728 AC: 11073 AN: 152158 Hom.: 471 Cov.: 33

Gnomad AFR AF: 0.0652

Gnomad AMI AF: 0.0439

Gnomad AMR AF: 0.0598

Gnomad ASJ AF: 0.0435

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0207

Gnomad FIN AF: 0.0511

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.0945

Gnomad OTH AF: 0.0733

GnomAD4 exome AF: 0.0735 AC: 50460 AN: 686376 Hom.: 2246 AF XY: 0.0720 AC XY: 26640 AN XY: 370002

African (AFR) AF: 0.0670 AC: 1248 AN: 18632

American (AMR) AF: 0.0445 AC: 1909 AN: 42862

Ashkenazi Jewish (ASJ) AF: 0.0443 AC: 944 AN: 21316

East Asian (EAS) AF: 0.0000827 AC: 3 AN: 36274

South Asian (SAS) AF: 0.0218 AC: 1529 AN: 70098

European-Finnish (FIN) AF: 0.0552 AC: 2737 AN: 49550

Middle Eastern (MID) AF: 0.0717 AC: 288 AN: 4018

European-Non Finnish (NFE) AF: 0.0961 AC: 39287 AN: 408630

Other (OTH) AF: 0.0719 AC: 2515 AN: 34996

GnomAD4 genome AF: 0.0727 AC: 11072 AN: 152276 Hom.: 471 Cov.: 33 AF XY: 0.0696 AC XY: 5181 AN XY: 74456

African (AFR) AF: 0.0651 AC: 2704 AN: 41558

American (AMR) AF: 0.0598 AC: 915 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0435 AC: 151 AN: 3470

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5186

South Asian (SAS) AF: 0.0207 AC: 100 AN: 4824

European-Finnish (FIN) AF: 0.0511 AC: 542 AN: 10604

Middle Eastern (MID) AF: 0.126 AC: 37 AN: 294

European-Non Finnish (NFE) AF: 0.0945 AC: 6427 AN: 68024

Other (OTH) AF: 0.0726 AC: 153 AN: 2108

Alfa AF: 0.0493 Hom.: 43

Bravo AF: 0.0737

Asia WGS AF: 0.0160 AC: 54 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.72
DANN	Benign	0.70
PhyloP100		-1.5
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: rs17401652; hg19: chr22-26868490;