11-18279407-G-A

Variant names:

• chr11-18279407-G-A
• rs1046615
• NM_181507.2:c.*475C>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.*475C>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 0.334 in 170,026 control chromosomes in the GnomAD database, including 9,814 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (8954 hom., cov: 33)
  • Exomes 𝑓: 0.30 (860 hom.)
• Consequence: HPS5 NM_181507.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.372

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=-0.84).
• BP6: Variant 11-18279407-G-A is Benign according to our data. Variant chr11-18279407-G-A is described in ClinVar as [Benign]. Clinvar id is 303857.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.409 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPS5	NM_181507.2	c.*475C>T		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.*475C>T		3_prime_UTR_variant	Exon 23 of 23	1	NM_181507.2	ENSP00000265967.5
HPS5	ENST00000396253	c.*475C>T		3_prime_UTR_variant	Exon 22 of 22	1		ENSP00000379552.3
HPS5	ENST00000438420	c.*475C>T		3_prime_UTR_variant	Exon 22 of 22	1		ENSP00000399590.2
HPS5	ENST00000537258.1	c.*528C>T		downstream_gene_variant		5		ENSP00000437437.1

Frequencies

GnomAD3 genomes AF: 0.337 AC: 51210 AN: 151936 Hom.: 8947 Cov.: 33

Gnomad AFR AF: 0.415

Gnomad AMI AF: 0.151

Gnomad AMR AF: 0.294

Gnomad ASJ AF: 0.325

Gnomad EAS AF: 0.386

Gnomad SAS AF: 0.297

Gnomad FIN AF: 0.387

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.295

Gnomad OTH AF: 0.325

GnomAD4 exome AF: 0.304 AC: 5462 AN: 17972 Hom.: 860 Cov.: 0 AF XY: 0.303 AC XY: 2891 AN XY: 9546

Gnomad4 AFR exome AF: 0.343

Gnomad4 AMR exome AF: 0.316

Gnomad4 ASJ exome AF: 0.278

Gnomad4 EAS exome AF: 0.398

Gnomad4 SAS exome AF: 0.299

Gnomad4 FIN exome AF: 0.322

Gnomad4 NFE exome AF: 0.290

Gnomad4 OTH exome AF: 0.318

GnomAD4 genome AF: 0.337 AC: 51250 AN: 152054 Hom.: 8954 Cov.: 33 AF XY: 0.339 AC XY: 25193 AN XY: 74300

Gnomad4 AFR AF: 0.414

Gnomad4 AMR AF: 0.294

Gnomad4 ASJ AF: 0.325

Gnomad4 EAS AF: 0.386

Gnomad4 SAS AF: 0.297

Gnomad4 FIN AF: 0.387

Gnomad4 NFE AF: 0.295

Gnomad4 OTH AF: 0.326

Alfa AF: 0.307 Hom.: 9169

Bravo AF: 0.336

Asia WGS AF: 0.375 AC: 1302 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

Jan 12, 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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	3.0
DANN	Benign	0.29

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: rs1046615; hg19: chr11-18300954;