rs6440589

Variant names:

• chr3-149155200-G-A
• rs6440589
• NM_032383.5:c.1494G>A

Your query was ambiguous. Multiple possible variants found:

• chr3-149155200-G-A
• chr3-149155200-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_032383.5(HPS3):​c.1494G>A​(p.Gln498Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.452 in 1,539,766 control chromosomes in the GnomAD database, including 161,541 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.50 (19977 hom., cov: 32)
  • Exomes 𝑓: 0.45 (141564 hom.)
• Consequence: HPS3 NM_032383.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.264
• Publications: 20 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 3-149155200-G-A is Benign according to our data. Variant chr3-149155200-G-A is described in ClinVar as Benign. ClinVar VariationId is 163668.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.264 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.653 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPS3	NM_032383.5	MANE Select	c.1494G>A	p.Gln498Gln	synonymous	Exon 8 of 17	NP_115759.2
	HPS3	NM_001308258.2		c.999G>A	p.Gln333Gln	synonymous	Exon 7 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.1494G>A	p.Gln498Gln	synonymous	Exon 8 of 17	ENSP00000296051.2
	HPS3	ENST00000870872.1		c.1494G>A	p.Gln498Gln	synonymous	Exon 8 of 17	ENSP00000540931.1
	HPS3	ENST00000870871.1		c.1494G>A	p.Gln498Gln	synonymous	Exon 8 of 17	ENSP00000540930.1

Frequencies

GnomAD3 genomes AF: 0.502 AC: 76190 AN: 151860 Hom.: 19945 Cov.: 32

Gnomad AFR AF: 0.660

Gnomad AMI AF: 0.376

Gnomad AMR AF: 0.379

Gnomad ASJ AF: 0.389

Gnomad EAS AF: 0.367

Gnomad SAS AF: 0.511

Gnomad FIN AF: 0.473

Gnomad MID AF: 0.399

Gnomad NFE AF: 0.456

Gnomad OTH AF: 0.462

GnomAD2 exomes AF: 0.445 AC: 111431 AN: 250662 AF XY: 0.448

Gnomad AFR exome AF: 0.672

Gnomad AMR exome AF: 0.293

Gnomad ASJ exome AF: 0.400

Gnomad EAS exome AF: 0.365

Gnomad FIN exome AF: 0.464

Gnomad NFE exome AF: 0.454

Gnomad OTH exome AF: 0.445

GnomAD4 exome AF: 0.447 AC: 620305 AN: 1387788 Hom.: 141564 Cov.: 24 AF XY: 0.449 AC XY: 312084 AN XY: 694724

African (AFR) AF: 0.665 AC: 21159 AN: 31806

American (AMR) AF: 0.303 AC: 13526 AN: 44608

Ashkenazi Jewish (ASJ) AF: 0.399 AC: 10254 AN: 25694

East Asian (EAS) AF: 0.359 AC: 14128 AN: 39322

South Asian (SAS) AF: 0.504 AC: 42597 AN: 84546

European-Finnish (FIN) AF: 0.467 AC: 24899 AN: 53332

Middle Eastern (MID) AF: 0.408 AC: 2301 AN: 5638

European-Non Finnish (NFE) AF: 0.445 AC: 465054 AN: 1044892

Other (OTH) AF: 0.455 AC: 26387 AN: 57950

GnomAD4 genome AF: 0.502 AC: 76272 AN: 151978 Hom.: 19977 Cov.: 32 AF XY: 0.499 AC XY: 37091 AN XY: 74302

African (AFR) AF: 0.660 AC: 27338 AN: 41434

American (AMR) AF: 0.378 AC: 5773 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.389 AC: 1349 AN: 3468

East Asian (EAS) AF: 0.368 AC: 1902 AN: 5170

South Asian (SAS) AF: 0.512 AC: 2471 AN: 4822

European-Finnish (FIN) AF: 0.473 AC: 4995 AN: 10554

Middle Eastern (MID) AF: 0.398 AC: 117 AN: 294

European-Non Finnish (NFE) AF: 0.456 AC: 31012 AN: 67958

Other (OTH) AF: 0.463 AC: 975 AN: 2106

Alfa AF: 0.471 Hom.: 29830

Bravo AF: 0.498

Asia WGS AF: 0.451 AC: 1570 AN: 3478

EpiCase AF: 0.436

EpiControl AF: 0.438

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Hermansky-Pudlak syndrome 3 (2)
-	-	1	Hermansky-Pudlak syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.1
DANN	Benign	0.30
PhyloP100		-0.26
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs6440589; hg19: chr3-148872987; COSMIC: COSV56055838; COSMIC: COSV56055838;