11-18279582-A-G

Variant names:

• chr11-18279582-A-G
• rs12416821
• NM_181507.2:c.*300T>C

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.*300T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.321 in 416,040 control chromosomes in the GnomAD database, including 22,195 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (8805 hom., cov: 33)
  • Exomes 𝑓: 0.31 (13390 hom.)
• Consequence: HPS5 NM_181507.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.55

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=-0.82).
• BP6: Variant 11-18279582-A-G is Benign according to our data. Variant chr11-18279582-A-G is described in ClinVar as [Benign]. Clinvar id is 303861.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.407 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPS5	NM_181507.2	c.*300T>C		3_prime_UTR_variant	Exon 23 of 23	ENST00000349215.8	NP_852608.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HPS5	ENST00000349215	c.*300T>C		3_prime_UTR_variant	Exon 23 of 23	1	NM_181507.2	ENSP00000265967.5
HPS5	ENST00000396253	c.*300T>C		3_prime_UTR_variant	Exon 22 of 22	1		ENSP00000379552.3
HPS5	ENST00000438420	c.*300T>C		3_prime_UTR_variant	Exon 22 of 22	1		ENSP00000399590.2
HPS5	ENST00000537258.1	c.*353T>C		downstream_gene_variant		5		ENSP00000437437.1

Frequencies

GnomAD3 genomes AF: 0.336 AC: 50958 AN: 151770 Hom.: 8798 Cov.: 33

Gnomad AFR AF: 0.412

Gnomad AMI AF: 0.149

Gnomad AMR AF: 0.293

Gnomad ASJ AF: 0.326

Gnomad EAS AF: 0.383

Gnomad SAS AF: 0.296

Gnomad FIN AF: 0.382

Gnomad MID AF: 0.312

Gnomad NFE AF: 0.294

Gnomad OTH AF: 0.324

GnomAD4 exome AF: 0.313 AC: 82707 AN: 264152 Hom.: 13390 Cov.: 0 AF XY: 0.311 AC XY: 43886 AN XY: 141260

Gnomad4 AFR exome AF: 0.413

Gnomad4 AMR exome AF: 0.313

Gnomad4 ASJ exome AF: 0.328

Gnomad4 EAS exome AF: 0.396

Gnomad4 SAS exome AF: 0.297

Gnomad4 FIN exome AF: 0.375

Gnomad4 NFE exome AF: 0.298

Gnomad4 OTH exome AF: 0.313

GnomAD4 genome AF: 0.336 AC: 50998 AN: 151888 Hom.: 8805 Cov.: 33 AF XY: 0.337 AC XY: 25041 AN XY: 74228

Gnomad4 AFR AF: 0.412

Gnomad4 AMR AF: 0.293

Gnomad4 ASJ AF: 0.326

Gnomad4 EAS AF: 0.383

Gnomad4 SAS AF: 0.296

Gnomad4 FIN AF: 0.382

Gnomad4 NFE AF: 0.294

Gnomad4 OTH AF: 0.325

Alfa AF: 0.324 Hom.: 1778

Bravo AF: 0.336

Asia WGS AF: 0.375 AC: 1301 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Hermansky-Pudlak syndrome 5 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.82
CADD	Benign	0.31
DANN	Benign	0.50

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: rs12416821; hg19: chr11-18301129;