11-18279418-G-T

Position:

• chr11-18279418-G-T

Variant summary

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

The NM_181507.2(HPS5):​c.*464C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.37 in 169,528 control chromosomes in the GnomAD database, including 14,067 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (12296 hom., cov: 33)
  • Exomes 𝑓: 0.43 (1771 hom.)
• Consequence: HPS5 NM_181507.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.994

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 11-18279418-G-T is Benign according to our data. Variant chr11-18279418-G-T is described in ClinVar as [Benign]. Clinvar id is 303858.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.491 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HPS5	NM_181507.2	c.*464C>A		3_prime_UTR_variant	23/23	ENST00000349215.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HPS5	ENST00000349215.8	c.*464C>A		3_prime_UTR_variant	23/23	1	NM_181507.2	P1
HPS5	ENST00000396253.7	c.*464C>A		3_prime_UTR_variant	22/22	1
HPS5	ENST00000438420.6	c.*464C>A		3_prime_UTR_variant	22/22	1

Frequencies

GnomAD3 genomes AF: 0.364 AC: 55298 AN: 152026 Hom.: 12299 Cov.: 33

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.596

Gnomad AMR AF: 0.391

Gnomad ASJ AF: 0.330

Gnomad EAS AF: 0.354

Gnomad SAS AF: 0.446

Gnomad FIN AF: 0.458

Gnomad MID AF: 0.256

Gnomad NFE AF: 0.496

Gnomad OTH AF: 0.353

GnomAD4 exome AF: 0.432 AC: 7510 AN: 17384 Hom.: 1771 Cov.: 0 AF XY: 0.430 AC XY: 3988 AN XY: 9268

Gnomad4 AFR exome AF: 0.0794

Gnomad4 AMR exome AF: 0.390

Gnomad4 ASJ exome AF: 0.277

Gnomad4 EAS exome AF: 0.317

Gnomad4 SAS exome AF: 0.390

Gnomad4 FIN exome AF: 0.489

Gnomad4 NFE exome AF: 0.482

Gnomad4 OTH exome AF: 0.395

GnomAD4 genome AF: 0.363 AC: 55292 AN: 152144 Hom.: 12296 Cov.: 33 AF XY: 0.362 AC XY: 26952 AN XY: 74394

Gnomad4 AFR AF: 0.104

Gnomad4 AMR AF: 0.391

Gnomad4 ASJ AF: 0.330

Gnomad4 EAS AF: 0.354

Gnomad4 SAS AF: 0.446

Gnomad4 FIN AF: 0.458

Gnomad4 NFE AF: 0.496

Gnomad4 OTH AF: 0.349

Alfa AF: 0.410 Hom.: 3175

Bravo AF: 0.347

Asia WGS AF: 0.404 AC: 1403 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

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. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	9.1
DANN	Benign	0.71

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: rs1046611; hg19: chr11-18300965;