3-149129654-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_032383.5(HPS3):c.-70T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0315 in 1,225,622 control chromosomes in the GnomAD database, including 783 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (65 hom., cov: 33)
  • Exomes 𝑓: 0.033 (718 hom.)
• Consequence: HPS3 NM_032383.5 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.76

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 3-149129654-T-C is Benign according to our data. Variant chr3-149129654-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 343688.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0606 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HPS3	NM_032383.5	c.-70T>C		5_prime_UTR_variant	1/17	ENST00000296051.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HPS3	ENST00000296051.7	c.-70T>C		5_prime_UTR_variant	1/17	1	NM_032383.5	P1

Frequencies

GnomAD3 genomes AF: 0.0234 AC: 3561 AN: 152086 Hom.: 64 Cov.: 33

Gnomad AFR AF: 0.00562

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0198

Gnomad ASJ AF: 0.0346

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0661

Gnomad FIN AF: 0.0199

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0337

Gnomad OTH AF: 0.0320

GnomAD4 exome AF: 0.0327 AC: 35075 AN: 1073418 Hom.: 718 Cov.: 14 AF XY: 0.0340 AC XY: 17949 AN XY: 528536

Gnomad4 AFR exome AF: 0.00531

Gnomad4 AMR exome AF: 0.0169

Gnomad4 ASJ exome AF: 0.0435

Gnomad4 EAS exome AF: 0.0000631

Gnomad4 SAS exome AF: 0.0698

Gnomad4 FIN exome AF: 0.0248

Gnomad4 NFE exome AF: 0.0324

Gnomad4 OTH exome AF: 0.0329

GnomAD4 genome AF: 0.0234 AC: 3562 AN: 152204 Hom.: 65 Cov.: 33 AF XY: 0.0235 AC XY: 1746 AN XY: 74420

Gnomad4 AFR AF: 0.00561

Gnomad4 AMR AF: 0.0198

Gnomad4 ASJ AF: 0.0346

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.0666

Gnomad4 FIN AF: 0.0199

Gnomad4 NFE AF: 0.0337

Gnomad4 OTH AF: 0.0317

Alfa AF: 0.0290 Hom.: 35

Bravo AF: 0.0216

Asia WGS AF: 0.0210 AC: 75 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hermansky-Pudlak syndrome 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 09, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	6.6
Dann	Benign	0.62

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

Publications

LitVar

Other links and lift over

dbSNP: rs13089410; hg19: chr3-148847441;