NM_032383.5:c.2292+111_2292+112delGA

Variant names:

• chr3-149162442-CAG-C
• rs58796831
• NM_032383.5:c.2292+111_2292+112delGA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_032383.5(HPS3):​c.2292+111_2292+112delGA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.137 in 1,047,440 control chromosomes in the GnomAD database, including 10,883 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.17 (2558 hom., cov: 29)
  • Exomes 𝑓: 0.13 (8325 hom.)
• Consequence: HPS3 NM_032383.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.121
• Publications: 1 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 -10 ACMG points.

• BP6: Variant 3-149162442-CAG-C is Benign according to our data. Variant chr3-149162442-CAG-C is described in ClinVar as [Benign]. Clinvar id is 1268637.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.276 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPS3	NM_032383.5	c.2292+111_2292+112delGA		intron_variant	Intron 12 of 16	ENST00000296051.7	NP_115759.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HPS3	ENST00000296051.7	c.2292+111_2292+112delGA		intron_variant	Intron 12 of 16	1	NM_032383.5	ENSP00000296051.2

Frequencies

GnomAD3 genomes AF: 0.171 AC: 25965 AN: 151958 Hom.: 2555 Cov.: 29

Gnomad AFR AF: 0.281

Gnomad AMI AF: 0.0780

Gnomad AMR AF: 0.125

Gnomad ASJ AF: 0.154

Gnomad EAS AF: 0.0878

Gnomad SAS AF: 0.0961

Gnomad FIN AF: 0.147

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.132

Gnomad OTH AF: 0.158

GnomAD2 exomes AF: 0.132 AC: 22370 AN: 169590 AF XY: 0.130

Gnomad AFR exome AF: 0.287

Gnomad AMR exome AF: 0.101

Gnomad ASJ exome AF: 0.144

Gnomad EAS exome AF: 0.0806

Gnomad FIN exome AF: 0.153

Gnomad NFE exome AF: 0.136

Gnomad OTH exome AF: 0.150

GnomAD4 exome AF: 0.131 AC: 117201 AN: 895364 Hom.: 8325 AF XY: 0.129 AC XY: 59860 AN XY: 464852

African (AFR) AF: 0.284 AC: 6136 AN: 21588

American (AMR) AF: 0.101 AC: 3718 AN: 36658

Ashkenazi Jewish (ASJ) AF: 0.147 AC: 3271 AN: 22270

East Asian (EAS) AF: 0.0987 AC: 3442 AN: 34868

South Asian (SAS) AF: 0.0989 AC: 7019 AN: 70966

European-Finnish (FIN) AF: 0.151 AC: 7006 AN: 46490

Middle Eastern (MID) AF: 0.167 AC: 583 AN: 3498

European-Non Finnish (NFE) AF: 0.130 AC: 80324 AN: 617554

Other (OTH) AF: 0.137 AC: 5702 AN: 41472

GnomAD4 genome AF: 0.171 AC: 25972 AN: 152076 Hom.: 2558 Cov.: 29 AF XY: 0.169 AC XY: 12577 AN XY: 74330

African (AFR) AF: 0.280 AC: 11620 AN: 41436

American (AMR) AF: 0.125 AC: 1911 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.154 AC: 533 AN: 3472

East Asian (EAS) AF: 0.0876 AC: 454 AN: 5182

South Asian (SAS) AF: 0.0970 AC: 468 AN: 4826

European-Finnish (FIN) AF: 0.147 AC: 1552 AN: 10560

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.132 AC: 8991 AN: 67992

Other (OTH) AF: 0.155 AC: 328 AN: 2114

Alfa AF: 0.153 Hom.: 365

Bravo AF: 0.176

Asia WGS AF: 0.104 AC: 362 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.12
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: rs58796831; hg19: chr3-148880229;