rs2254913

Variant names:

• chr3-149150460-A-C
• rs2254913
• NM_032383.5:c.1164-139A>C

Your query was ambiguous. Multiple possible variants found:

• chr3-149150460-A-C
• chr3-149150460-A-T

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.1164-139A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.662 in 710,720 control chromosomes in the GnomAD database, including 158,619 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.70 (37791 hom., cov: 31)
  • Exomes 𝑓: 0.65 (120828 hom.)
• Consequence: HPS3 NM_032383.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.56
• Publications: 4 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.02).
• BP6: Variant 3-149150460-A-C is Benign according to our data. Variant chr3-149150460-A-C is described in ClinVar as Benign. ClinVar VariationId is 1185217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.85 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.1164-139A>C		intron	N/A	NP_115759.2
	HPS3	NM_001308258.2		c.669-139A>C		intron	N/A	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.1164-139A>C		intron	N/A	ENSP00000296051.2	Q969F9-1
	HPS3	ENST00000870872.1		c.1164-139A>C		intron	N/A	ENSP00000540931.1
	HPS3	ENST00000870871.1		c.1164-139A>C		intron	N/A	ENSP00000540930.1

Frequencies

GnomAD3 genomes AF: 0.696 AC: 105684 AN: 151878 Hom.: 37734 Cov.: 31

Gnomad AFR AF: 0.857

Gnomad AMI AF: 0.499

Gnomad AMR AF: 0.582

Gnomad ASJ AF: 0.560

Gnomad EAS AF: 0.534

Gnomad SAS AF: 0.793

Gnomad FIN AF: 0.732

Gnomad MID AF: 0.532

Gnomad NFE AF: 0.636

Gnomad OTH AF: 0.630

GnomAD4 exome AF: 0.652 AC: 364397 AN: 558724 Hom.: 120828 AF XY: 0.660 AC XY: 198570 AN XY: 301022

African (AFR) AF: 0.855 AC: 13513 AN: 15796

American (AMR) AF: 0.561 AC: 19373 AN: 34514

Ashkenazi Jewish (ASJ) AF: 0.564 AC: 11094 AN: 19668

East Asian (EAS) AF: 0.532 AC: 16894 AN: 31732

South Asian (SAS) AF: 0.781 AC: 48348 AN: 61912

European-Finnish (FIN) AF: 0.718 AC: 33035 AN: 45998

Middle Eastern (MID) AF: 0.545 AC: 1316 AN: 2414

European-Non Finnish (NFE) AF: 0.637 AC: 201454 AN: 316498

Other (OTH) AF: 0.642 AC: 19370 AN: 30192

GnomAD4 genome AF: 0.696 AC: 105797 AN: 151996 Hom.: 37791 Cov.: 31 AF XY: 0.699 AC XY: 51870 AN XY: 74252

African (AFR) AF: 0.857 AC: 35558 AN: 41482

American (AMR) AF: 0.581 AC: 8893 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.560 AC: 1944 AN: 3472

East Asian (EAS) AF: 0.533 AC: 2740 AN: 5136

South Asian (SAS) AF: 0.793 AC: 3811 AN: 4804

European-Finnish (FIN) AF: 0.732 AC: 7727 AN: 10550

Middle Eastern (MID) AF: 0.520 AC: 153 AN: 294

European-Non Finnish (NFE) AF: 0.636 AC: 43178 AN: 67940

Other (OTH) AF: 0.633 AC: 1339 AN: 2114

Alfa AF: 0.652 Hom.: 89312

Bravo AF: 0.685

Asia WGS AF: 0.698 AC: 2428 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.28
DANN	Benign	0.65
PhyloP100		-2.6
Mutation Taster		=100/0	polymorphism (auto)

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: rs2254913; hg19: chr3-148868247; COSMIC: COSV56056367;