rs141883346

Variant names:

• chr3-149129774-C-T
• rs141883346
• NM_032383.5:c.51C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Moderate BP6 BP7

The ENST00000296051.7(HPS3):​c.51C>T​(p.Pro17Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00116 in 1,608,694 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00090 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (1 hom.)
• Consequence: HPS3 ENST00000296051.7 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.103
• Publications: 2 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, ClinGen, Labcorp Genetics (formerly Invitae)
• Hermansky-Pudlak syndrome without pulmonary fibrosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BP6: Variant 3-149129774-C-T is Benign according to our data. Variant chr3-149129774-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 227429.
• BP7: Synonymous conserved (PhyloP=0.103 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000296051.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPS3	NM_032383.5	MANE Select	c.51C>T	p.Pro17Pro	synonymous	Exon 1 of 17	NP_115759.2
	HPS3	NM_001308258.2		c.51C>T	p.Pro17Pro	synonymous	Exon 1 of 16	NP_001295187.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPS3	ENST00000296051.7	TSL:1 MANE Select	c.51C>T	p.Pro17Pro	synonymous	Exon 1 of 17	ENSP00000296051.2
	HPS3	ENST00000460120.5	TSL:2	c.51C>T	p.Pro17Pro	synonymous	Exon 1 of 16	ENSP00000418230.1
	HPS3	ENST00000462030.5	TSL:2	n.137C>T		non_coding_transcript_exon	Exon 1 of 7

Frequencies

GnomAD3 genomes AF: 0.000900 AC: 137 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00163

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000838 AC: 199 AN: 237482 AF XY: 0.000785

Gnomad AFR exome AF: 0.000265

Gnomad AMR exome AF: 0.000379

Gnomad ASJ exome AF: 0.000102

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000742

Gnomad NFE exome AF: 0.00154

Gnomad OTH exome AF: 0.000509

GnomAD4 exome AF: 0.00119 AC: 1730 AN: 1456382 Hom.: 1 Cov.: 31 AF XY: 0.00117 AC XY: 847 AN XY: 724552

African (AFR) AF: 0.000120 AC: 4 AN: 33404

American (AMR) AF: 0.000426 AC: 19 AN: 44614

Ashkenazi Jewish (ASJ) AF: 0.000192 AC: 5 AN: 26042

East Asian (EAS) AF: 0.00 AC: 0 AN: 39648

South Asian (SAS) AF: 0.0000465 AC: 4 AN: 86100

European-Finnish (FIN) AF: 0.000896 AC: 45 AN: 50232

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5176

European-Non Finnish (NFE) AF: 0.00143 AC: 1589 AN: 1111010

Other (OTH) AF: 0.00106 AC: 64 AN: 60156

GnomAD4 genome AF: 0.000899 AC: 137 AN: 152312 Hom.: 0 Cov.: 32 AF XY: 0.000886 AC XY: 66 AN XY: 74484

African (AFR) AF: 0.000241 AC: 10 AN: 41564

American (AMR) AF: 0.000653 AC: 10 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00163 AC: 111 AN: 68022

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.00102 Hom.: 0

Bravo AF: 0.000756

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00164

EpiControl AF: 0.00107

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Hermansky-Pudlak syndrome (1)
-	1	-	Hermansky-Pudlak syndrome 3 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	14
DANN	Benign	0.96
PhyloP100		0.10
PromoterAI		-0.0035	Neutral
Mutation Taster		=100/0	polymorphism

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: rs141883346; hg19: chr3-148847561; COSMIC: COSV99937754;