chr3-149167290-C-G

Variant names:

• chr3-149167290-C-G
• rs2681092
• NM_032383.5:c.2796+50C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_032383.5(HPS3):​c.2796+50C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000016 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HPS3 NM_032383.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.213
• Publications: 11 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).

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.2796+50C>G		intron	N/A	NP_115759.2
	HPS3	NM_001308258.2		c.2301+50C>G		intron	N/A	NP_001295187.1	G5E9V4
	CP	NR_046371.2		n.2843-1240G>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPS3	ENST00000296051.7	TSL:1 MANE Select	c.2796+50C>G		intron	N/A	ENSP00000296051.2	Q969F9-1
	HPS3	ENST00000870872.1		c.2781+50C>G		intron	N/A	ENSP00000540931.1
	HPS3	ENST00000870871.1		c.2742+50C>G		intron	N/A	ENSP00000540930.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000156 AC: 2 AN: 1278568 Hom.: 0 Cov.: 18 AF XY: 0.00000156 AC XY: 1 AN XY: 639844

African (AFR) AF: 0.00 AC: 0 AN: 29358

American (AMR) AF: 0.00 AC: 0 AN: 37234

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24538

East Asian (EAS) AF: 0.00 AC: 0 AN: 36146

South Asian (SAS) AF: 0.00 AC: 0 AN: 78550

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48290

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4110

European-Non Finnish (NFE) AF: 0.00000103 AC: 1 AN: 966256

Other (OTH) AF: 0.0000185 AC: 1 AN: 54086

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.0
DANN	Benign	0.32
PhyloP100		0.21

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: rs2681092; hg19: chr3-148885077;