rs140443498

Variant names:

• chr3-149160228-G-A
• rs140443498
• NM_032383.5:c.2055G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_032383.5(HPS3):​c.2055G>A​(p.Leu685Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00456 in 1,613,840 control chromosomes in the GnomAD database, including 21 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. L685L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0029 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0047 (19 hom.)
• Consequence: HPS3 NM_032383.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.29
• Publications: 0 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 3-149160228-G-A is Benign according to our data. Variant chr3-149160228-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 226653.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.29 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00293 (446/152290) while in subpopulation NFE AF = 0.00475 (323/68022). AF 95% confidence interval is 0.00432. There are 2 homozygotes in GnomAd4. There are 209 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPS3	NM_032383.5	MANE Select	c.2055G>A	p.Leu685Leu	synonymous	Exon 11 of 17	NP_115759.2
	HPS3	NM_001308258.2		c.1560G>A	p.Leu520Leu	synonymous	Exon 10 of 16	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.2055G>A	p.Leu685Leu	synonymous	Exon 11 of 17	ENSP00000296051.2	Q969F9-1
	HPS3	ENST00000870872.1		c.2055G>A	p.Leu685Leu	synonymous	Exon 11 of 17	ENSP00000540931.1
	HPS3	ENST00000870871.1		c.2055G>A	p.Leu685Leu	synonymous	Exon 11 of 17	ENSP00000540930.1

Frequencies

GnomAD3 genomes AF: 0.00293 AC: 446 AN: 152172 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00500

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00475

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00308 AC: 772 AN: 250788 AF XY: 0.00308

Gnomad AFR exome AF: 0.000988

Gnomad AMR exome AF: 0.00104

Gnomad ASJ exome AF: 0.000795

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00471

Gnomad NFE exome AF: 0.00483

Gnomad OTH exome AF: 0.00262

GnomAD4 exome AF: 0.00473 AC: 6907 AN: 1461550 Hom.: 19 Cov.: 31 AF XY: 0.00471 AC XY: 3423 AN XY: 727068

African (AFR) AF: 0.000598 AC: 20 AN: 33456

American (AMR) AF: 0.00103 AC: 46 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.00138 AC: 36 AN: 26126

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39684

South Asian (SAS) AF: 0.00133 AC: 115 AN: 86256

European-Finnish (FIN) AF: 0.00502 AC: 268 AN: 53418

Middle Eastern (MID) AF: 0.000868 AC: 5 AN: 5762

European-Non Finnish (NFE) AF: 0.00559 AC: 6214 AN: 1111802

Other (OTH) AF: 0.00335 AC: 202 AN: 60374

GnomAD4 genome AF: 0.00293 AC: 446 AN: 152290 Hom.: 2 Cov.: 33 AF XY: 0.00281 AC XY: 209 AN XY: 74458

African (AFR) AF: 0.000794 AC: 33 AN: 41564

American (AMR) AF: 0.000981 AC: 15 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4824

European-Finnish (FIN) AF: 0.00500 AC: 53 AN: 10610

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

European-Non Finnish (NFE) AF: 0.00475 AC: 323 AN: 68022

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.00341 Hom.: 0

Bravo AF: 0.00289

EpiCase AF: 0.00431

EpiControl AF: 0.00528

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	6.9
DANN	Benign	0.79
PhyloP100		1.3
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: rs140443498; hg19: chr3-148878015;