3-149129746-AC-A

Variant names:

• chr3-149129746-AC-A
• rs2108111799
• NM_032383.5:c.26delC

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_032383.5(HPS3):​c.26delC​(p.Pro9ArgfsTer69) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,452,616 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. P9P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: HPS3 NM_032383.5 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.51
• 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]

HPS3 Gene-Disease associations (from GenCC):

• Hermansky-Pudlak syndrome 3

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen
• Hermansky-Pudlak syndrome without pulmonary fibrosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 225 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-149129746-AC-A is Pathogenic according to our data. Variant chr3-149129746-AC-A is described in ClinVar as Pathogenic. ClinVar VariationId is 1073245.Status of the report is criteria_provided_single_submitter, 1 stars.

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.26delC	p.Pro9ArgfsTer69	frameshift	Exon 1 of 17	NP_115759.2
	HPS3	NM_001308258.2		c.26delC	p.Pro9ArgfsTer106	frameshift	Exon 1 of 16	NP_001295187.1	G5E9V4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPS3	ENST00000296051.7	TSL:1 MANE Select	c.26delC	p.Pro9ArgfsTer69	frameshift	Exon 1 of 17	ENSP00000296051.2	Q969F9-1
	HPS3	ENST00000870872.1		c.26delC	p.Pro9ArgfsTer69	frameshift	Exon 1 of 17	ENSP00000540931.1
	HPS3	ENST00000870871.1		c.26delC	p.Pro9ArgfsTer69	frameshift	Exon 1 of 17	ENSP00000540930.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1452616 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 722434

African (AFR) AF: 0.00 AC: 0 AN: 33332

American (AMR) AF: 0.00 AC: 0 AN: 44528

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25966

East Asian (EAS) AF: 0.00 AC: 0 AN: 39584

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85978

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48244

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4826

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110164

Other (OTH) AF: 0.00 AC: 0 AN: 59994

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.5

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: rs2108111799; hg19: chr3-148847533;