chr3-149163339-G-A

Variant names:

• chr3-149163339-G-A
• rs7636389
• NM_032383.5:c.2481+461G>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.2481+461G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.132 in 152,088 control chromosomes in the GnomAD database, including 1,631 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 0.13 (1631 hom., cov: 32)
• Consequence: HPS3 NM_032383.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.258
• Publications: 5 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: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• disorder of iron metabolism and transport

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.222 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.2481+461G>A		intron	N/A	NP_115759.2
	HPS3	NM_001308258.2		c.1986+461G>A		intron	N/A	NP_001295187.1
	CP	NR_046371.2		n.2948-464C>T		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPS3	ENST00000296051.7	TSL:1 MANE Select	c.2481+461G>A		intron	N/A	ENSP00000296051.2
	HPS3	ENST00000870872.1		c.2466+461G>A		intron	N/A	ENSP00000540931.1
	HPS3	ENST00000870871.1		c.2481+461G>A		intron	N/A	ENSP00000540930.1

Frequencies

GnomAD3 genomes AF: 0.132 AC: 20068 AN: 151970 Hom.: 1628 Cov.: 32

Gnomad AFR AF: 0.226

Gnomad AMI AF: 0.0802

Gnomad AMR AF: 0.101

Gnomad ASJ AF: 0.136

Gnomad EAS AF: 0.0849

Gnomad SAS AF: 0.0507

Gnomad FIN AF: 0.106

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.0961

Gnomad OTH AF: 0.121

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

GnomAD4 genome AF: 0.132 AC: 20074 AN: 152088 Hom.: 1631 Cov.: 32 AF XY: 0.130 AC XY: 9693 AN XY: 74370

African (AFR) AF: 0.226 AC: 9358 AN: 41436

American (AMR) AF: 0.101 AC: 1538 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.136 AC: 471 AN: 3472

East Asian (EAS) AF: 0.0848 AC: 438 AN: 5168

South Asian (SAS) AF: 0.0516 AC: 249 AN: 4826

European-Finnish (FIN) AF: 0.106 AC: 1127 AN: 10598

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.0961 AC: 6532 AN: 67982

Other (OTH) AF: 0.120 AC: 254 AN: 2116

Alfa AF: 0.103 Hom.: 492

Bravo AF: 0.138

Asia WGS AF: 0.0870 AC: 301 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	6.4
DANN	Benign	0.64
PhyloP100		0.26
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs7636389; hg19: chr3-148881126;