3-149141387-A-G

Variant names:

• chr3-149141387-A-G
• rs114029765
• NM_032383.5:c.970+7A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_032383.5(HPS3):​c.970+7A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0377 in 1,606,870 control chromosomes in the GnomAD database, including 1,367 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (74 hom., cov: 31)
  • Exomes 𝑓: 0.039 (1293 hom.)
• Consequence: HPS3 NM_032383.5 splice_region, intron
• Scores: Splicing: ADA: 0.000008553
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -2.35
• Publications: 5 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 3-149141387-A-G is Benign according to our data. Variant chr3-149141387-A-G is described in ClinVar as Benign. ClinVar VariationId is 178776.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0574 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPS3	NM_032383.5	MANE Select	c.970+7A>G		splice_region intron	N/A	NP_115759.2
	HPS3	NM_001308258.2		c.475+7A>G		splice_region intron	N/A	NP_001295187.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPS3	ENST00000296051.7	TSL:1 MANE Select	c.970+7A>G		splice_region intron	N/A	ENSP00000296051.2
	HPS3	ENST00000870872.1		c.970+7A>G		splice_region intron	N/A	ENSP00000540931.1
	HPS3	ENST00000870871.1		c.970+7A>G		splice_region intron	N/A	ENSP00000540930.1

Frequencies

GnomAD3 genomes AF: 0.0270 AC: 4103 AN: 152104 Hom.: 75 Cov.: 31

Gnomad AFR AF: 0.00908

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0178

Gnomad ASJ AF: 0.0245

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0634

Gnomad FIN AF: 0.0415

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0374

Gnomad OTH AF: 0.0321

GnomAD2 exomes AF: 0.0346 AC: 8698 AN: 251228 AF XY: 0.0385

Gnomad AFR exome AF: 0.00678

Gnomad AMR exome AF: 0.0157

Gnomad ASJ exome AF: 0.0219

Gnomad EAS exome AF: 0.000217

Gnomad FIN exome AF: 0.0475

Gnomad NFE exome AF: 0.0389

Gnomad OTH exome AF: 0.0424

GnomAD4 exome AF: 0.0388 AC: 56481 AN: 1454650 Hom.: 1293 Cov.: 31 AF XY: 0.0400 AC XY: 28950 AN XY: 724138

African (AFR) AF: 0.00738 AC: 246 AN: 33334

American (AMR) AF: 0.0163 AC: 728 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0219 AC: 572 AN: 26104

East Asian (EAS) AF: 0.000176 AC: 7 AN: 39674

South Asian (SAS) AF: 0.0705 AC: 6065 AN: 86078

European-Finnish (FIN) AF: 0.0474 AC: 2534 AN: 53408

Middle Eastern (MID) AF: 0.0738 AC: 425 AN: 5760

European-Non Finnish (NFE) AF: 0.0396 AC: 43796 AN: 1105412

Other (OTH) AF: 0.0350 AC: 2108 AN: 60162

GnomAD4 genome AF: 0.0269 AC: 4098 AN: 152220 Hom.: 74 Cov.: 31 AF XY: 0.0276 AC XY: 2058 AN XY: 74448

African (AFR) AF: 0.00908 AC: 377 AN: 41538

American (AMR) AF: 0.0178 AC: 272 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0245 AC: 85 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5176

South Asian (SAS) AF: 0.0632 AC: 305 AN: 4824

European-Finnish (FIN) AF: 0.0415 AC: 439 AN: 10588

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0374 AC: 2545 AN: 68004

Other (OTH) AF: 0.0303 AC: 64 AN: 2110

Alfa AF: 0.0305 Hom.: 60

Bravo AF: 0.0235

Asia WGS AF: 0.0220 AC: 76 AN: 3478

EpiCase AF: 0.0374

EpiControl AF: 0.0389

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.79
DANN	Benign	0.38
PhyloP100		-2.4
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000086
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.20		Position offset: 31

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs114029765; hg19: chr3-148859174;