11-18279439-A-T

Variant names:

• chr11-18279439-A-T
• rs74602396
• NM_181507.2:c.*443T>A

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.*443T>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 0.0235 in 178,604 control chromosomes in the GnomAD database, including 145 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (144 hom., cov: 33)
  • Exomes 𝑓: 0.0040 (1 hom.)
• Consequence: HPS5 NM_181507.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.181

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 11-18279439-A-T is Benign according to our data. Variant chr11-18279439-A-T is described in ClinVar as [Benign]. Clinvar id is 303859.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0824 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPS5	NM_181507.2	c.*443T>A		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.*443T>A		3_prime_UTR_variant	Exon 23 of 23	1	NM_181507.2	ENSP00000265967.5
HPS5	ENST00000396253	c.*443T>A		3_prime_UTR_variant	Exon 22 of 22	1		ENSP00000379552.3
HPS5	ENST00000438420	c.*443T>A		3_prime_UTR_variant	Exon 22 of 22	1		ENSP00000399590.2
HPS5	ENST00000537258.1	c.*496T>A		downstream_gene_variant		5		ENSP00000437437.1

Frequencies

GnomAD3 genomes AF: 0.0269 AC: 4089 AN: 152182 Hom.: 143 Cov.: 33

Gnomad AFR AF: 0.0848

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0202

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00288

Gnomad OTH AF: 0.0268

GnomAD4 exome AF: 0.00399 AC: 105 AN: 26304 Hom.: 1 Cov.: 0 AF XY: 0.00363 AC XY: 50 AN XY: 13766

Gnomad4 AFR exome AF: 0.0856

Gnomad4 AMR exome AF: 0.0124

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000269

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00159

Gnomad4 OTH exome AF: 0.00522

GnomAD4 genome AF: 0.0269 AC: 4095 AN: 152300 Hom.: 144 Cov.: 33 AF XY: 0.0268 AC XY: 1993 AN XY: 74472

Gnomad4 AFR AF: 0.0847

Gnomad4 AMR AF: 0.0201

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00287

Gnomad4 OTH AF: 0.0265

Alfa AF: 0.0158 Hom.: 12

Bravo AF: 0.0303

Asia WGS AF: 0.00577 AC: 20 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 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. -

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	-0.82
CADD	Benign	2.1
DANN	Benign	0.68

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: rs74602396; hg19: chr11-18300986;