rs2254913

Positions:

• chr3-149150460-A-C
• chr3-149150460-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_032383.5(HPS3):​c.1164-139A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.662 in 710,720 control chromosomes in the GnomAD database, including 158,619 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.70 (37791 hom., cov: 31)
  • Exomes 𝑓: 0.65 (120828 hom.)
• Consequence: HPS3 NM_032383.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.56

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.02).
• BP6: Variant 3-149150460-A-C is Benign according to our data. Variant chr3-149150460-A-C is described in ClinVar as [Benign]. Clinvar id is 1185217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.85 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HPS3	NM_032383.5	c.1164-139A>C		intron_variant		ENST00000296051.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HPS3	ENST00000296051.7	c.1164-139A>C		intron_variant		1	NM_032383.5	P1
HPS3	ENST00000460120.5	c.669-139A>C		intron_variant		2
HPS3	ENST00000462030.5	n.1763-139A>C		intron_variant, non_coding_transcript_variant		2
HPS3	ENST00000486530.1	n.1197-139A>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.696 AC: 105684 AN: 151878 Hom.: 37734 Cov.: 31

Gnomad AFR AF: 0.857

Gnomad AMI AF: 0.499

Gnomad AMR AF: 0.582

Gnomad ASJ AF: 0.560

Gnomad EAS AF: 0.534

Gnomad SAS AF: 0.793

Gnomad FIN AF: 0.732

Gnomad MID AF: 0.532

Gnomad NFE AF: 0.636

Gnomad OTH AF: 0.630

GnomAD4 exome AF: 0.652 AC: 364397 AN: 558724 Hom.: 120828 AF XY: 0.660 AC XY: 198570 AN XY: 301022

Gnomad4 AFR exome AF: 0.855

Gnomad4 AMR exome AF: 0.561

Gnomad4 ASJ exome AF: 0.564

Gnomad4 EAS exome AF: 0.532

Gnomad4 SAS exome AF: 0.781

Gnomad4 FIN exome AF: 0.718

Gnomad4 NFE exome AF: 0.637

Gnomad4 OTH exome AF: 0.642

GnomAD4 genome AF: 0.696 AC: 105797 AN: 151996 Hom.: 37791 Cov.: 31 AF XY: 0.699 AC XY: 51870 AN XY: 74252

Gnomad4 AFR AF: 0.857

Gnomad4 AMR AF: 0.581

Gnomad4 ASJ AF: 0.560

Gnomad4 EAS AF: 0.533

Gnomad4 SAS AF: 0.793

Gnomad4 FIN AF: 0.732

Gnomad4 NFE AF: 0.636

Gnomad4 OTH AF: 0.633

Alfa AF: 0.635 Hom.: 49766

Bravo AF: 0.685

Asia WGS AF: 0.698 AC: 2428 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hermansky-Pudlak syndrome 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 09, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.28
DANN	Benign	0.65

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

Publications

LitVar

Other links and lift over

dbSNP: rs2254913; hg19: chr3-148868247; COSMIC: COSV56056367;