rs3752590

Variant names:

• chr22-26451846-A-T
• rs3752590
• NM_022081.6:c.*1387T>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_022081.6(HPS4):​c.*1387T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00121 in 152,222 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0012 (4 hom., cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HPS4 NM_022081.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.32
• 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 22-26451846-A-T is Benign according to our data. Variant chr22-26451846-A-T is described in ClinVar as Benign. ClinVar VariationId is 900908.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00121 (184/152222) while in subpopulation EAS AF = 0.0326 (168/5158). AF 95% confidence interval is 0.0285. There are 4 homozygotes in GnomAd4. There are 114 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

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.*1387T>A		3_prime_UTR	Exon 14 of 14	NP_071364.4
	HPS4	NM_001349900.2		c.*1387T>A		3_prime_UTR	Exon 15 of 15	NP_001336829.1	F1LLU8
	HPS4	NM_001349901.1		c.*1387T>A		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.*1387T>A		3_prime_UTR	Exon 14 of 14	ENSP00000381213.2	Q9NQG7-1
	HPS4	ENST00000422379.3	TSL:5	c.*1387T>A		3_prime_UTR	Exon 15 of 15	ENSP00000415081.3	F1LLU8
	HPS4	ENST00000473782.2	TSL:2	c.*1387T>A		3_prime_UTR	Exon 15 of 15	ENSP00000514223.1	Q9NQG7-1

Frequencies

GnomAD3 genomes AF: 0.00122 AC: 185 AN: 152104 Hom.: 4 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0325

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00144

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 3014 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 1642

African (AFR) AF: 0.00 AC: 0 AN: 28

American (AMR) AF: 0.00 AC: 0 AN: 436

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 36

East Asian (EAS) AF: 0.00 AC: 0 AN: 50

South Asian (SAS) AF: 0.00 AC: 0 AN: 278

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 66

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 8

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1994

Other (OTH) AF: 0.00 AC: 0 AN: 118

GnomAD4 genome AF: 0.00121 AC: 184 AN: 152222 Hom.: 4 Cov.: 31 AF XY: 0.00153 AC XY: 114 AN XY: 74422

African (AFR) AF: 0.00 AC: 0 AN: 41544

American (AMR) AF: 0.000131 AC: 2 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.0326 AC: 168 AN: 5158

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68012

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.000139 Hom.: 0

Bravo AF: 0.00177

Asia WGS AF: 0.00895 AC: 31 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Hermansky-Pudlak syndrome 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.6
DANN	Benign	0.79
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs3752590; hg19: chr22-26847812;