rs61755718

chr11-18283808-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_181507.2(HPS5):c.3045G>A(p.Met1015Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00612 in 1,607,300 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1015V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0051 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0062 (32 hom.)
• Consequence: HPS5 NM_181507.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.71

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 (MetaRNN=0.0052384734).
• BP6: Variant 11-18283808-C-T is Benign according to our data. Variant chr11-18283808-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 262986.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-18283808-C-T is described in Lovd as [Benign]. Variant chr11-18283808-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00512 (779/152272) while in subpopulation AMR AF= 0.00922 (141/15290). AF 95% confidence interval is 0.00798. There are 6 homozygotes in gnomad4. There are 364 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HPS5	NM_181507.2	c.3045G>A	p.Met1015Ile	missense_variant	21/23	ENST00000349215.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HPS5	ENST00000349215.8	c.3045G>A	p.Met1015Ile	missense_variant	21/23	1	NM_181507.2	P1

Frequencies

GnomAD3 genomes AF: 0.00512 AC: 779 AN: 152154 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.000989

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00923

Gnomad ASJ AF: 0.00663

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00245

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00762

Gnomad OTH AF: 0.00622

GnomAD3 exomes AF: 0.00520 AC: 1306 AN: 251098 Hom.: 6 AF XY: 0.00545 AC XY: 740 AN XY: 135758

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.00437

Gnomad ASJ exome AF: 0.00526

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00209

Gnomad FIN exome AF: 0.00286

Gnomad NFE exome AF: 0.00798

Gnomad OTH exome AF: 0.00750

GnomAD4 exome AF: 0.00622 AC: 9057 AN: 1455028 Hom.: 32 Cov.: 29 AF XY: 0.00630 AC XY: 4563 AN XY: 724354

Gnomad4 AFR exome AF: 0.000899

Gnomad4 AMR exome AF: 0.00481

Gnomad4 ASJ exome AF: 0.00560

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00237

Gnomad4 FIN exome AF: 0.00352

Gnomad4 NFE exome AF: 0.00710

Gnomad4 OTH exome AF: 0.00623

GnomAD4 genome AF: 0.00512 AC: 779 AN: 152272 Hom.: 6 Cov.: 32 AF XY: 0.00489 AC XY: 364 AN XY: 74458

Gnomad4 AFR AF: 0.000987

Gnomad4 AMR AF: 0.00922

Gnomad4 ASJ AF: 0.00663

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.00245

Gnomad4 NFE AF: 0.00762

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.00703 Hom.: 6

Bravo AF: 0.00538

TwinsUK AF: 0.00782 AC: 29

ALSPAC AF: 0.00727 AC: 28

ESP6500AA AF: 0.00205 AC: 9

ESP6500EA AF: 0.00885 AC: 76

ExAC AF: 0.00532 AC: 646

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00889

EpiControl AF: 0.00842

ClinVar

Significance: Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 08, 2017	- -

Hermansky-Pudlak syndrome 5 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	May 18, 2015	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	HPS5: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	22
Dann	Benign	0.96
Eigen	Benign	-0.21
Eigen_PC	Benign	0.062
FATHMM_MKL	Uncertain	0.89	D
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.0052	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.94	N;N;N;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.32	N;N;N;N
REVEL	Benign	0.061
Sift	Benign	0.27	T;T;T;T
Sift4G	Benign	0.26	T;T;T;D
Polyphen		0.0020	.;B;.;.
Vest4		0.37
MutPred		0.19		.;Loss of sheet (P = 0.1158);.;.;
MVP		0.44
MPC		0.059
ClinPred		0.0068	T
GERP RS		5.1
Varity_R		0.11
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs61755718; hg19: chr11-18305355;