rs2689229

Variant names:

• chr3-149150201-C-A
• rs2689229
• NM_032383.5:c.1164-398C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_032383.5(HPS3):​c.1164-398C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.477 in 151,922 control chromosomes in the GnomAD database, including 17,576 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 0.48 (17576 hom., cov: 31)
• Consequence: HPS3 NM_032383.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.762
• Publications: 3 publications found

Genes affected

HPS3 (HGNC:15597): (HPS3 biogenesis of lysosomal organelles complex 2 subunit 1) This gene encodes a protein containing a potential clathrin-binding motif, consensus dileucine signals, and tyrosine-based sorting signals for targeting to vesicles of lysosomal lineage. The encoded protein may play a role in organelle biogenesis associated with melanosomes, platelet dense granules, and lysosomes. Mutations in this gene are associated with Hermansky-Pudlak syndrome type 3. [provided by RefSeq, Apr 2015]

HPS3 Gene-Disease associations (from GenCC):

• Hermansky-Pudlak syndrome 3

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• Hermansky-Pudlak syndrome without 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=-0.95).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.543 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPS3	NM_032383.5	c.1164-398C>A		intron_variant	Intron 5 of 16	ENST00000296051.7	NP_115759.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HPS3	ENST00000296051.7	c.1164-398C>A		intron_variant	Intron 5 of 16	1	NM_032383.5	ENSP00000296051.2
HPS3	ENST00000460120.5	c.669-398C>A		intron_variant	Intron 4 of 15	2		ENSP00000418230.1
HPS3	ENST00000462030.5	n.1763-398C>A		intron_variant	Intron 5 of 6	2
HPS3	ENST00000486530.1	n.1197-398C>A		intron_variant	Intron 5 of 6	5

Frequencies

GnomAD3 genomes AF: 0.476 AC: 72328 AN: 151804 Hom.: 17540 Cov.: 31

Gnomad AFR AF: 0.549

Gnomad AMI AF: 0.390

Gnomad AMR AF: 0.421

Gnomad ASJ AF: 0.344

Gnomad EAS AF: 0.434

Gnomad SAS AF: 0.540

Gnomad FIN AF: 0.559

Gnomad MID AF: 0.332

Gnomad NFE AF: 0.441

Gnomad OTH AF: 0.421

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

GnomAD4 genome AF: 0.477 AC: 72416 AN: 151922 Hom.: 17576 Cov.: 31 AF XY: 0.480 AC XY: 35669 AN XY: 74266

African (AFR) AF: 0.549 AC: 22739 AN: 41414

American (AMR) AF: 0.421 AC: 6437 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.344 AC: 1194 AN: 3472

East Asian (EAS) AF: 0.434 AC: 2238 AN: 5162

South Asian (SAS) AF: 0.540 AC: 2592 AN: 4804

European-Finnish (FIN) AF: 0.559 AC: 5896 AN: 10544

Middle Eastern (MID) AF: 0.340 AC: 100 AN: 294

European-Non Finnish (NFE) AF: 0.441 AC: 29976 AN: 67924

Other (OTH) AF: 0.421 AC: 890 AN: 2112

Alfa AF: 0.467 Hom.: 3005

Bravo AF: 0.467

Asia WGS AF: 0.505 AC: 1756 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	4.8
DANN	Benign	0.56
PhyloP100		0.76
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: rs2689229; hg19: chr3-148867988;