rs78336249

chr3-149162256-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_032383.5(HPS3):c.2215G>A(p.Gly739Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0145 in 1,613,918 control chromosomes in the GnomAD database, including 223 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (15 hom., cov: 33)
  • Exomes 𝑓: 0.015 (208 hom.)
• Consequence: HPS3 NM_032383.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 5.81

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 (MetaRNN=0.009357303).
• BP6: Variant 3-149162256-G-A is Benign according to our data. Variant chr3-149162256-G-A is described in ClinVar as [Benign]. Clinvar id is 226654.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0101 (1545/152270) while in subpopulation NFE AF= 0.0167 (1135/68030). AF 95% confidence interval is 0.0159. There are 15 homozygotes in gnomad4. There are 707 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HPS3	NM_032383.5	c.2215G>A	p.Gly739Arg	missense_variant	12/17	ENST00000296051.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HPS3	ENST00000296051.7	c.2215G>A	p.Gly739Arg	missense_variant	12/17	1	NM_032383.5	P1
HPS3	ENST00000460120.5	c.1720G>A	p.Gly574Arg	missense_variant	11/16	2
HPS3	ENST00000460822.1	c.343G>A	p.Gly115Arg	missense_variant, NMD_transcript_variant	2/8	2

Frequencies

GnomAD3 genomes AF: 0.0102 AC: 1545 AN: 152152 Hom.: 15 Cov.: 33

Gnomad AFR AF: 0.00282

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00845

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0124

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0167

Gnomad OTH AF: 0.00958

GnomAD3 exomes AF: 0.00967 AC: 2428 AN: 251124 Hom.: 24 AF XY: 0.00903 AC XY: 1226 AN XY: 135700

Gnomad AFR exome AF: 0.00308

Gnomad AMR exome AF: 0.00655

Gnomad ASJ exome AF: 0.00318

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00111

Gnomad FIN exome AF: 0.0125

Gnomad NFE exome AF: 0.0154

Gnomad OTH exome AF: 0.0113

GnomAD4 exome AF: 0.0149 AC: 21822 AN: 1461648 Hom.: 208 Cov.: 32 AF XY: 0.0145 AC XY: 10568 AN XY: 727144

Gnomad4 AFR exome AF: 0.00230

Gnomad4 AMR exome AF: 0.00683

Gnomad4 ASJ exome AF: 0.00310

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00115

Gnomad4 FIN exome AF: 0.0129

Gnomad4 NFE exome AF: 0.0178

Gnomad4 OTH exome AF: 0.0126

GnomAD4 genome AF: 0.0101 AC: 1545 AN: 152270 Hom.: 15 Cov.: 33 AF XY: 0.00950 AC XY: 707 AN XY: 74436

Gnomad4 AFR AF: 0.00282

Gnomad4 AMR AF: 0.00843

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0124

Gnomad4 NFE AF: 0.0167

Gnomad4 OTH AF: 0.00948

Alfa AF: 0.0136 Hom.: 28

Bravo AF: 0.00949

TwinsUK AF: 0.0178 AC: 66

ALSPAC AF: 0.0192 AC: 74

ESP6500AA AF: 0.00454 AC: 20

ESP6500EA AF: 0.0157 AC: 135

ExAC AF: 0.00955 AC: 1159

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0142

EpiControl AF: 0.0136

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 21, 2013

Gly739Arg in exon 12 of HPS3: This variant is not expected to have clinical sign ificance because it has been identified in 1.6% (135/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs78336249). -

Hermansky-Pudlak syndrome 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Hermansky-Pudlak syndrome Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Nov 11, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.37	T;T
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.80	T;T
MetaRNN	Benign	0.0094	T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	0.95	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-2.5	N;D
REVEL	Benign	0.25
Sift	Benign	0.035	D;T
Sift4G	Uncertain	0.0050	D;D
Polyphen		0.32	B;P
Vest4		0.37
MutPred		0.65		Gain of solvent accessibility (P = 0.019);.;
MVP		0.85
MPC		0.15
ClinPred		0.018	T
GERP RS		5.1
Varity_R		0.24
gMVP		0.70

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: rs78336249; hg19: chr3-148880043;