11-18311430-C-T

Position:

chr11-18311430-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_181507.2(HPS5):c.241G>A(p.Ala81Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00224 in 1,608,378 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0016 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0023 ( 6 hom. )

Consequence

HPS5
NM_181507.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:3

Conservation

PhyloP100: 1.27

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.016596079).

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00156 (237/152028) while in subpopulation SAS AF= 0.00375 (18/4804). AF 95% confidence interval is 0.00242. There are 0 homozygotes in gnomad4. There are 101 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HPS5	NM_181507.2 linkuse as main transcript	c.241G>A	p.Ala81Thr	missense_variant	4/23	ENST00000349215.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HPS5	ENST00000349215.8 linkuse as main transcript	c.241G>A	p.Ala81Thr	missense_variant	4/23	1	NM_181507.2	P1	Q9UPZ3-1
HPS5	ENST00000396253.7 linkuse as main transcript	c.-102G>A		5_prime_UTR_variant	3/22	1			Q9UPZ3-2
HPS5	ENST00000438420.6 linkuse as main transcript	c.-102G>A		5_prime_UTR_variant	3/22	1			Q9UPZ3-2
HPS5	ENST00000531848.1 linkuse as main transcript	c.-102G>A		5_prime_UTR_variant	3/11	5

Frequencies

GnomAD3 genomes

AF:

0.00155

AC:

236

AN:

151916

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000411

Gnomad AMI

AF:

0.00220

Gnomad AMR

AF:

0.00184

Gnomad ASJ

AF:

0.000577

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00374

Gnomad FIN

AF:

0.000190

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00231

Gnomad OTH

AF:

0.00431

GnomAD3 exomes

AF:

0.00165

AC:

412

AN:

249934

Hom.:

AF XY:

0.00185

AC XY:

250

AN XY:

135228

show subpopulations

Gnomad AFR exome

AF:

0.000617

Gnomad AMR exome

AF:

0.00165

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000549

Gnomad SAS exome

AF:

0.00307

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.00212

Gnomad OTH exome

AF:

0.00132

GnomAD4 exome

AF:

0.00231

AC:

3366

AN:

1456350

Hom.:

Cov.:

AF XY:

0.00247

AC XY:

1789

AN XY:

724918

show subpopulations

Gnomad4 AFR exome

AF:

0.000449

Gnomad4 AMR exome

AF:

0.00179

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.00323

Gnomad4 FIN exome

AF:

0.000169

Gnomad4 NFE exome

AF:

0.00255

Gnomad4 OTH exome

AF:

0.00258

GnomAD4 genome

AF:

0.00156

AC:

237

AN:

152028

Hom.:

Cov.:

AF XY:

0.00136

AC XY:

101

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.000410

Gnomad4 AMR

AF:

0.00190

Gnomad4 ASJ

AF:

0.000577

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00375

Gnomad4 FIN

AF:

0.000190

Gnomad4 NFE

AF:

0.00231

Gnomad4 OTH

AF:

0.00427

Alfa

AF:

0.00217

Hom.:

Bravo

AF:

0.00173

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.000682

AC:

ESP6500EA

AF:

0.00186

AC:

ExAC

AF:

0.00152

AC:

185

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hermansky-Pudlak syndrome 5

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 09, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The HPS5 p.Ala81Thr variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs147053126) and ClinVar (classified as a VUS by Illumina Clinical Services and University of Chicago Genetics Services Laboratory for Hermansky-Pudlak Syndrome). The variant was identified in control databases in 444 of 281254 chromosomes (2 homozygous) at a frequency of 0.001579 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: South Asian in 93 of 30314 chromosomes (freq: 0.003068), European (non-Finnish) in 265 of 128834 chromosomes (freq: 0.002057), Latino in 56 of 34854 chromosomes (freq: 0.001607), Other in 11 of 7166 chromosomes (freq: 0.001535), African in 13 of 24908 chromosomes (freq: 0.000522), European (Finnish) in 5 of 25058 chromosomes (freq: 0.0002) and East Asian in 1 of 19768 chromosomes (freq: 0.000051); it was not observed in the Ashkenazi Jewish population. The p.Ala81 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

May 03, 2016

- -

HPS5-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 21, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.15

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.16

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.040

MetaRNN

Benign

0.017

MetaSVM

Benign

-0.81

MutationAssessor

Benign

1.8

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.99

REVEL

Benign

0.24

Sift

Benign

0.23

Sift4G

Uncertain

0.016

Polyphen

0.98

Vest4

0.48

MVP

0.72

MPC

0.16

ClinPred

0.017

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.10

gMVP

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

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