3-149134668-G-A

Variant names:

• chr3-149134668-G-A
• rs4681169
• NM_032383.5:c.217+4728G>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.217+4728G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.368 in 151,968 control chromosomes in the GnomAD database, including 11,152 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 0.37 (11152 hom., cov: 32)
• Consequence: HPS3 NM_032383.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0600
• Publications: 7 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.521 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032383.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPS3	NM_032383.5	MANE Select	c.217+4728G>A		intron	N/A	NP_115759.2
	HPS3	NM_001308258.2		c.217+4728G>A		intron	N/A	NP_001295187.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPS3	ENST00000296051.7	TSL:1 MANE Select	c.217+4728G>A		intron	N/A	ENSP00000296051.2
	HPS3	ENST00000460120.5	TSL:2	c.217+4728G>A		intron	N/A	ENSP00000418230.1
	HPS3	ENST00000462030.5	TSL:2	n.816+4215G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.368 AC: 55826 AN: 151850 Hom.: 11115 Cov.: 32

Gnomad AFR AF: 0.527

Gnomad AMI AF: 0.168

Gnomad AMR AF: 0.341

Gnomad ASJ AF: 0.300

Gnomad EAS AF: 0.166

Gnomad SAS AF: 0.389

Gnomad FIN AF: 0.307

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.307

Gnomad OTH AF: 0.359

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

GnomAD4 genome AF: 0.368 AC: 55917 AN: 151968 Hom.: 11152 Cov.: 32 AF XY: 0.364 AC XY: 27052 AN XY: 74288

African (AFR) AF: 0.527 AC: 21832 AN: 41406

American (AMR) AF: 0.341 AC: 5210 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.300 AC: 1041 AN: 3472

East Asian (EAS) AF: 0.165 AC: 855 AN: 5182

South Asian (SAS) AF: 0.388 AC: 1865 AN: 4804

European-Finnish (FIN) AF: 0.307 AC: 3240 AN: 10556

Middle Eastern (MID) AF: 0.313 AC: 92 AN: 294

European-Non Finnish (NFE) AF: 0.307 AC: 20861 AN: 67954

Other (OTH) AF: 0.365 AC: 768 AN: 2104

Alfa AF: 0.318 Hom.: 13184

Bravo AF: 0.376

Asia WGS AF: 0.324 AC: 1131 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.83
DANN	Benign	0.64
PhyloP100		-0.060
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: rs4681169; hg19: chr3-148852455;