11-18279078-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_181507.2(HPS5):c.*804C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.165 in 152,180 control chromosomes in the GnomAD database, including 2,285 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.16 (2285 hom., cov: 33)
  • Failed GnomAD Quality Control
• Consequence: HPS5 NM_181507.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.450

Genes affected

HPS5 (HGNC:17022): (HPS5 biogenesis of lysosomal organelles complex 2 subunit 2) This gene encodes a protein that may play a role in organelle biogenesis associated with melanosomes, platelet dense granules, and lysosomes. This protein interacts with Hermansky-Pudlak syndrome 6 protein and may interact with the cytoplasmic domain of integrin, alpha-3. Mutations in this gene are associated with Hermansky-Pudlak syndrome type 5. Multiple transcript variants encoding two distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 11-18279078-G-A is Benign according to our data. Variant chr11-18279078-G-A is described in ClinVar as [Benign]. Clinvar id is 303853.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.193 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HPS5	NM_181507.2	c.*804C>T		3_prime_UTR_variant	23/23	ENST00000349215.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HPS5	ENST00000349215.8	c.*804C>T		3_prime_UTR_variant	23/23	1	NM_181507.2	P1
HPS5	ENST00000396253.7	c.*804C>T		3_prime_UTR_variant	22/22	1
HPS5	ENST00000438420.6	c.*804C>T		3_prime_UTR_variant	22/22	1

Frequencies

GnomAD3 genomes AF: 0.165 AC: 25097 AN: 152062 Hom.: 2282 Cov.: 33

Gnomad AFR AF: 0.197

Gnomad AMI AF: 0.0691

Gnomad AMR AF: 0.103

Gnomad ASJ AF: 0.162

Gnomad EAS AF: 0.000963

Gnomad SAS AF: 0.0598

Gnomad FIN AF: 0.203

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.176

Gnomad OTH AF: 0.147

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

GnomAD4 genome AF: 0.165 AC: 25107 AN: 152180 Hom.: 2285 Cov.: 33 AF XY: 0.161 AC XY: 11986 AN XY: 74402

Gnomad4 AFR AF: 0.197

Gnomad4 AMR AF: 0.103

Gnomad4 ASJ AF: 0.162

Gnomad4 EAS AF: 0.000965

Gnomad4 SAS AF: 0.0599

Gnomad4 FIN AF: 0.203

Gnomad4 NFE AF: 0.176

Gnomad4 OTH AF: 0.145

Alfa AF: 0.177 Hom.: 236

Bravo AF: 0.159

Asia WGS AF: 0.0360 AC: 128 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hermansky-Pudlak syndrome 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	1.7
Dann	Benign	0.34

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: rs1046628; hg19: chr11-18300625;