rs34197730

Variant names:

• chr3-149155185-G-A
• rs34197730
• NM_032383.5:c.1479G>A

Your query was ambiguous. Multiple possible variants found:

• chr3-149155185-G-A
• chr3-149155185-G-C
• chr3-149155185-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_032383.5(HPS3):​c.1479G>A​(p.Thr493Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0344 in 1,590,148 control chromosomes in the GnomAD database, including 1,092 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T493T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.031 (79 hom., cov: 33)
  • Exomes 𝑓: 0.035 (1013 hom.)
• Consequence: HPS3 NM_032383.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.19
• Publications: 8 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=-0.71).
• BP6: Variant 3-149155185-G-A is Benign according to our data. Variant chr3-149155185-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 178778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.19 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0312 (4752/152212) while in subpopulation SAS AF = 0.0452 (218/4822). AF 95% confidence interval is 0.0403. There are 79 homozygotes in GnomAd4. There are 2331 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 79 AR gene

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.1479G>A	p.Thr493Thr	synonymous	Exon 8 of 17	NP_115759.2
	HPS3	NM_001308258.2		c.984G>A	p.Thr328Thr	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.1479G>A	p.Thr493Thr	synonymous	Exon 8 of 17	ENSP00000296051.2
	HPS3	ENST00000460120.5	TSL:2	c.984G>A	p.Thr328Thr	synonymous	Exon 7 of 16	ENSP00000418230.1

Frequencies

GnomAD3 genomes AF: 0.0313 AC: 4756 AN: 152094 Hom.: 80 Cov.: 33

Gnomad AFR AF: 0.0296

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0203

Gnomad ASJ AF: 0.0179

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0452

Gnomad FIN AF: 0.0407

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0358

Gnomad OTH AF: 0.0316

GnomAD2 exomes AF: 0.0322 AC: 8065 AN: 250838 AF XY: 0.0344

Gnomad AFR exome AF: 0.0312

Gnomad AMR exome AF: 0.0170

Gnomad ASJ exome AF: 0.0165

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0459

Gnomad NFE exome AF: 0.0359

Gnomad OTH exome AF: 0.0393

GnomAD4 exome AF: 0.0348 AC: 49981 AN: 1437936 Hom.: 1013 Cov.: 26 AF XY: 0.0356 AC XY: 25488 AN XY: 716904

African (AFR) AF: 0.0295 AC: 973 AN: 32974

American (AMR) AF: 0.0176 AC: 788 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.0152 AC: 396 AN: 26000

East Asian (EAS) AF: 0.000152 AC: 6 AN: 39594

South Asian (SAS) AF: 0.0509 AC: 4360 AN: 85734

European-Finnish (FIN) AF: 0.0455 AC: 2426 AN: 53364

Middle Eastern (MID) AF: 0.0549 AC: 315 AN: 5740

European-Non Finnish (NFE) AF: 0.0356 AC: 38834 AN: 1090204

Other (OTH) AF: 0.0316 AC: 1883 AN: 59634

GnomAD4 genome AF: 0.0312 AC: 4752 AN: 152212 Hom.: 79 Cov.: 33 AF XY: 0.0313 AC XY: 2331 AN XY: 74428

African (AFR) AF: 0.0295 AC: 1225 AN: 41538

American (AMR) AF: 0.0203 AC: 310 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0179 AC: 62 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5186

South Asian (SAS) AF: 0.0452 AC: 218 AN: 4822

European-Finnish (FIN) AF: 0.0407 AC: 431 AN: 10590

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

European-Non Finnish (NFE) AF: 0.0358 AC: 2432 AN: 68006

Other (OTH) AF: 0.0298 AC: 63 AN: 2112

Alfa AF: 0.0298 Hom.: 63

Bravo AF: 0.0296

Asia WGS AF: 0.0160 AC: 56 AN: 3478

EpiCase AF: 0.0339

EpiControl AF: 0.0352

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely 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	-0.71
CADD	Benign	2.7
DANN	Benign	0.35
PhyloP100		-1.2
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs34197730; hg19: chr3-148872972;