NM_032383.5:c.2887+19dupT

Variant names:

• chr3-149167992-A-AT
• rs397710976
• NM_032383.5:c.2887+19dupT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_032383.5(HPS3):​c.2887+19dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.40 (13267 hom., cov: 0)
  • Exomes 𝑓: 0.27 (23925 hom.)
• Consequence: HPS3 NM_032383.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.188
• Publications: 0 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen, Ambry Genetics, Orphanet
• disorder of iron metabolism and transport

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 3-149167992-A-AT is Benign according to our data. Variant chr3-149167992-A-AT is described in ClinVar as Benign. ClinVar VariationId is 343715.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.611 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPS3	NM_032383.5	MANE Select	c.2887+19dupT		intron	N/A	NP_115759.2
	HPS3	NM_001308258.2		c.2392+19dupT		intron	N/A	NP_001295187.1	G5E9V4
	CP	NR_046371.2		n.2843-1943dupA		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPS3	ENST00000296051.7	TSL:1 MANE Select	c.2887+19dupT		intron	N/A	ENSP00000296051.2	Q969F9-1
	HPS3	ENST00000870872.1		c.2872+19dupT		intron	N/A	ENSP00000540931.1
	HPS3	ENST00000870871.1		c.2833+19dupT		intron	N/A	ENSP00000540930.1

Frequencies

GnomAD3 genomes AF: 0.396 AC: 59442 AN: 150124 Hom.: 13246 Cov.: 0

Gnomad AFR AF: 0.617

Gnomad AMI AF: 0.312

Gnomad AMR AF: 0.277

Gnomad ASJ AF: 0.219

Gnomad EAS AF: 0.372

Gnomad SAS AF: 0.322

Gnomad FIN AF: 0.391

Gnomad MID AF: 0.260

Gnomad NFE AF: 0.308

Gnomad OTH AF: 0.351

GnomAD2 exomes AF: 0.325 AC: 67084 AN: 206140 AF XY: 0.321

Gnomad AFR exome AF: 0.549

Gnomad AMR exome AF: 0.258

Gnomad ASJ exome AF: 0.241

Gnomad EAS exome AF: 0.363

Gnomad FIN exome AF: 0.361

Gnomad NFE exome AF: 0.309

Gnomad OTH exome AF: 0.315

GnomAD4 exome AF: 0.266 AC: 301993 AN: 1135664 Hom.: 23925 Cov.: 18 AF XY: 0.268 AC XY: 154544 AN XY: 576444

African (AFR) AF: 0.501 AC: 11800 AN: 23574

American (AMR) AF: 0.224 AC: 9186 AN: 40964

Ashkenazi Jewish (ASJ) AF: 0.215 AC: 4935 AN: 22994

East Asian (EAS) AF: 0.330 AC: 11681 AN: 35426

South Asian (SAS) AF: 0.283 AC: 21429 AN: 75646

European-Finnish (FIN) AF: 0.339 AC: 17071 AN: 50312

Middle Eastern (MID) AF: 0.218 AC: 1072 AN: 4916

European-Non Finnish (NFE) AF: 0.254 AC: 211314 AN: 833266

Other (OTH) AF: 0.278 AC: 13505 AN: 48566

GnomAD4 genome AF: 0.396 AC: 59523 AN: 150240 Hom.: 13267 Cov.: 0 AF XY: 0.395 AC XY: 28963 AN XY: 73340

African (AFR) AF: 0.617 AC: 25301 AN: 40984

American (AMR) AF: 0.277 AC: 4168 AN: 15070

Ashkenazi Jewish (ASJ) AF: 0.219 AC: 753 AN: 3432

East Asian (EAS) AF: 0.372 AC: 1906 AN: 5124

South Asian (SAS) AF: 0.324 AC: 1547 AN: 4780

European-Finnish (FIN) AF: 0.391 AC: 3990 AN: 10206

Middle Eastern (MID) AF: 0.264 AC: 76 AN: 288

European-Non Finnish (NFE) AF: 0.308 AC: 20772 AN: 67366

Other (OTH) AF: 0.349 AC: 727 AN: 2082

Alfa AF: 0.224 Hom.: 479

Bravo AF: 0.395

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Hermansky-Pudlak syndrome (2)
-	-	2	not provided (2)
-	-	1	Deficiency of ferroxidase (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.19
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: rs397710976; hg19: chr3-148885779;