rs3752589

Variant names:

• chr22-26451620-G-T
• rs3752589
• NM_022081.6:c.*1613C>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.*1613C>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 0.887 in 152,260 control chromosomes in the GnomAD database, including 60,489 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.89 (60468 hom., cov: 32)
  • Exomes 𝑓: 1.0 (21 hom.)
• Consequence: HPS4 NM_022081.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.09
• Publications: 6 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=-1.03).
• BP6: Variant 22-26451620-G-T is Benign according to our data. Variant chr22-26451620-G-T is described in ClinVar as [Benign]. Clinvar id is 340965.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.945 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPS4	NM_022081.6	c.*1613C>A		3_prime_UTR_variant	Exon 14 of 14	ENST00000398145.7	NP_071364.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HPS4	ENST00000398145.7	c.*1613C>A		3_prime_UTR_variant	Exon 14 of 14	1	NM_022081.6	ENSP00000381213.2

Frequencies

GnomAD3 genomes AF: 0.887 AC: 134981 AN: 152100 Hom.: 60452 Cov.: 32

Gnomad AFR AF: 0.779

Gnomad AMI AF: 0.886

Gnomad AMR AF: 0.802

Gnomad ASJ AF: 0.980

Gnomad EAS AF: 0.852

Gnomad SAS AF: 0.925

Gnomad FIN AF: 0.991

Gnomad MID AF: 0.934

Gnomad NFE AF: 0.951

Gnomad OTH AF: 0.897

GnomAD4 exome AF: 1.00 AC: 42 AN: 42 Hom.: 21 Cov.: 0 AF XY: 1.00 AC XY: 34 AN XY: 34

African (AFR) AC: 0 AN: 0

American (AMR) AF: 1.00 AC: 2 AN: 2

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 1.00 AC: 2 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 1.00 AC: 34 AN: 34

Other (OTH) AF: 1.00 AC: 4 AN: 4

GnomAD4 genome AF: 0.887 AC: 135048 AN: 152218 Hom.: 60468 Cov.: 32 AF XY: 0.886 AC XY: 65974 AN XY: 74428

African (AFR) AF: 0.779 AC: 32318 AN: 41502

American (AMR) AF: 0.801 AC: 12250 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.980 AC: 3403 AN: 3472

East Asian (EAS) AF: 0.852 AC: 4409 AN: 5176

South Asian (SAS) AF: 0.925 AC: 4464 AN: 4824

European-Finnish (FIN) AF: 0.991 AC: 10510 AN: 10610

Middle Eastern (MID) AF: 0.932 AC: 274 AN: 294

European-Non Finnish (NFE) AF: 0.951 AC: 64722 AN: 68028

Other (OTH) AF: 0.894 AC: 1890 AN: 2114

Alfa AF: 0.924 Hom.: 81961

Bravo AF: 0.867

Asia WGS AF: 0.859 AC: 2989 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Hermansky-Pudlak syndrome Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.45
DANN	Benign	0.59
PhyloP100		-1.1
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: rs3752589; hg19: chr22-26847586;