rs78336249

Variant names:

• chr3-149162256-G-A
• rs78336249
• NM_032383.5:c.2215G>A

Variant summary

Our verdict is Benign. The variant received -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. 13/21 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:5
• Conservation: PhyloP100: 5.81
• 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]

CP (HGNC:2295): (ceruloplasmin) The protein encoded by this gene is a metalloprotein that binds most of the copper in plasma and is involved in the peroxidation of Fe(II)transferrin to Fe(III) transferrin. Mutations in this gene cause aceruloplasminemia, which results in iron accumulation and tissue damage, and is associated with diabetes and neurologic abnormalities. Two transcript variants, one protein-coding and the other not protein-coding, have been found for this gene. [provided by RefSeq, Feb 2012]

CP Gene-Disease associations (from GenCC):

• aceruloplasminemia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, Ambry Genetics
• disorder of iron metabolism and transport

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 15 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPS3	NM_032383.5	MANE Select	c.2215G>A	p.Gly739Arg	missense	Exon 12 of 17	NP_115759.2
	HPS3	NM_001308258.2		c.1720G>A	p.Gly574Arg	missense	Exon 11 of 16	NP_001295187.1	G5E9V4
	CP	NR_046371.2		n.*158C>T		downstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPS3	ENST00000296051.7	TSL:1 MANE Select	c.2215G>A	p.Gly739Arg	missense	Exon 12 of 17	ENSP00000296051.2	Q969F9-1
	HPS3	ENST00000870872.1		c.2215G>A	p.Gly739Arg	missense	Exon 12 of 17	ENSP00000540931.1
	HPS3	ENST00000870871.1		c.2215G>A	p.Gly739Arg	missense	Exon 12 of 17	ENSP00000540930.1

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

GnomAD2 exomes AF: 0.00967 AC: 2428 AN: 251124 AF XY: 0.00903

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 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

African (AFR) AF: 0.00230 AC: 77 AN: 33464

American (AMR) AF: 0.00683 AC: 305 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.00310 AC: 81 AN: 26130

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39688

South Asian (SAS) AF: 0.00115 AC: 99 AN: 86258

European-Finnish (FIN) AF: 0.0129 AC: 691 AN: 53420

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5764

European-Non Finnish (NFE) AF: 0.0178 AC: 19797 AN: 1111864

Other (OTH) AF: 0.0126 AC: 760 AN: 60376

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

African (AFR) AF: 0.00282 AC: 117 AN: 41552

American (AMR) AF: 0.00843 AC: 129 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.0124 AC: 131 AN: 10606

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0167 AC: 1135 AN: 68030

Other (OTH) AF: 0.00948 AC: 20 AN: 2110

Alfa AF: 0.0134 Hom.: 57

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Hermansky-Pudlak syndrome (1)
-	-	1	Hermansky-Pudlak syndrome 3 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0094	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	0.95	L
PhyloP100		5.8
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.25
Sift	Benign	0.035	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.32	B
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
Mutation Taster		=93/7	polymorphism

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: rs78336249; hg19: chr3-148880043;