rs2689232

Variant names:

• chr3-149150574-C-T
• rs2689232
• NM_032383.5:c.1164-25C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_032383.5(HPS3):​c.1164-25C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.22 in 1,606,278 control chromosomes in the GnomAD database, including 41,521 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.18 (3072 hom., cov: 31)
  • Exomes 𝑓: 0.22 (38449 hom.)
• Consequence: HPS3 NM_032383.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.541
• Publications: 8 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 -18 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 3 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP6: Variant 3-149150574-C-T is Benign according to our data. Variant chr3-149150574-C-T is described in ClinVar as Benign. ClinVar VariationId is 262023.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.287 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPS3	NM_032383.5	c.1164-25C>T		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.1164-25C>T		intron_variant	Intron 5 of 16	1	NM_032383.5	ENSP00000296051.2
HPS3	ENST00000460120.5	c.669-25C>T		intron_variant	Intron 4 of 15	2		ENSP00000418230.1
HPS3	ENST00000462030.5	n.1763-25C>T		intron_variant	Intron 5 of 6	2
HPS3	ENST00000486530.1	n.1197-25C>T		intron_variant	Intron 5 of 6	5

Frequencies

GnomAD3 genomes AF: 0.181 AC: 27466 AN: 152034 Hom.: 3075 Cov.: 31

Gnomad AFR AF: 0.0657

Gnomad AMI AF: 0.309

Gnomad AMR AF: 0.156

Gnomad ASJ AF: 0.118

Gnomad EAS AF: 0.275

Gnomad SAS AF: 0.300

Gnomad FIN AF: 0.282

Gnomad MID AF: 0.105

Gnomad NFE AF: 0.228

Gnomad OTH AF: 0.149

GnomAD2 exomes AF: 0.212 AC: 53155 AN: 250742 AF XY: 0.220

Gnomad AFR exome AF: 0.0612

Gnomad AMR exome AF: 0.136

Gnomad ASJ exome AF: 0.122

Gnomad EAS exome AF: 0.278

Gnomad FIN exome AF: 0.267

Gnomad NFE exome AF: 0.224

Gnomad OTH exome AF: 0.183

GnomAD4 exome AF: 0.224 AC: 326012 AN: 1454126 Hom.: 38449 Cov.: 30 AF XY: 0.227 AC XY: 164363 AN XY: 723866

African (AFR) AF: 0.0577 AC: 1923 AN: 33320

American (AMR) AF: 0.137 AC: 6141 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.123 AC: 3213 AN: 26078

East Asian (EAS) AF: 0.269 AC: 10668 AN: 39656

South Asian (SAS) AF: 0.292 AC: 25093 AN: 86076

European-Finnish (FIN) AF: 0.264 AC: 14112 AN: 53366

Middle Eastern (MID) AF: 0.0956 AC: 534 AN: 5586

European-Non Finnish (NFE) AF: 0.228 AC: 251690 AN: 1105244

Other (OTH) AF: 0.210 AC: 12638 AN: 60116

GnomAD4 genome AF: 0.181 AC: 27468 AN: 152152 Hom.: 3072 Cov.: 31 AF XY: 0.185 AC XY: 13720 AN XY: 74362

African (AFR) AF: 0.0657 AC: 2728 AN: 41552

American (AMR) AF: 0.156 AC: 2379 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.118 AC: 408 AN: 3468

East Asian (EAS) AF: 0.276 AC: 1425 AN: 5170

South Asian (SAS) AF: 0.300 AC: 1448 AN: 4824

European-Finnish (FIN) AF: 0.282 AC: 2981 AN: 10556

Middle Eastern (MID) AF: 0.106 AC: 31 AN: 292

European-Non Finnish (NFE) AF: 0.228 AC: 15473 AN: 67986

Other (OTH) AF: 0.149 AC: 313 AN: 2106

Alfa AF: 0.198 Hom.: 632

Bravo AF: 0.163

Asia WGS AF: 0.256 AC: 892 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hermansky-Pudlak syndrome 3 Benign:1

Jul 10, 2021

Genome-Nilou Lab

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	-0.28
CADD	Benign	17
DANN	Benign	0.77
PhyloP100		0.54
BranchPoint Hunter		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		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: rs2689232; hg19: chr3-148868361; COSMIC: COSV56052875;