rs7636389

Positions:

• chr3-149163339-G-A

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HPS3	NM_032383.5	c.2481+461G>A		intron_variant		ENST00000296051.7	NP_115759.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HPS3	ENST00000296051.7	c.2481+461G>A		intron_variant		1	NM_032383.5	ENSP00000296051	P1

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

Gnomad4 AFR AF: 0.226

Gnomad4 AMR AF: 0.101

Gnomad4 ASJ AF: 0.136

Gnomad4 EAS AF: 0.0848

Gnomad4 SAS AF: 0.0516

Gnomad4 FIN AF: 0.106

Gnomad4 NFE AF: 0.0961

Gnomad4 OTH AF: 0.120

Alfa AF: 0.104 Hom.: 451

Bravo AF: 0.138

Asia WGS AF: 0.0870 AC: 301 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	6.4
DANN	Benign	0.64

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

Publications

LitVar

Other links and lift over

dbSNP: rs7636389; hg19: chr3-148881126;