11-18283808-C-T

Position:

chr11-18283808-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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 (★★).

Frequency

Genomes: 𝑓 0.0051 ( 6 hom., cov: 32)

Exomes 𝑓: 0.0062 ( 32 hom. )

Consequence

HPS5
NM_181507.2 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 1.71

Variant links:

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]

HPS5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HPS5	NM_181507.2 linkuse as main transcript	c.3045G>A	p.Met1015Ile	missense_variant	21/23	ENST00000349215.8	NP_852608.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HPS5	ENST00000349215.8 linkuse as main transcript	c.3045G>A	p.Met1015Ile	missense_variant	21/23	1	NM_181507.2	ENSP00000265967	P1	Q9UPZ3-1

Frequencies

GnomAD3 genomes

AF:

0.00512

AC:

779

AN:

152154

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00545

AC XY:

740

AN XY:

135758

show subpopulations

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.:

Cov.:

AF XY:

0.00630

AC XY:

4563

AN XY:

724354

show subpopulations

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.:

Cov.:

AF XY:

0.00489

AC XY:

364

AN XY:

74458

show subpopulations

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.:

Bravo

AF:

0.00538

TwinsUK

AF:

0.00782

AC:

ALSPAC

AF:

0.00727

AC:

ESP6500AA

AF:

0.00205

AC:

ESP6500EA

AF:

0.00885

AC:

ExAC

AF:

0.00532

AC:

646

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00889

EpiControl

AF:

0.00842

ClinVar

Significance: Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

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

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	HPS5: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.10

.;T;.;.

Eigen

Benign

-0.21

Eigen_PC

Benign

0.062

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.79

.;T;T;T

M_CAP

Benign

0.0034

MetaRNN

Benign

0.0052

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.76

.;N;.;.

MutationTaster

Benign

0.94

N;N;N;N

PrimateAI

Benign

0.44

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over