NM_181507.2:c.1249C>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_181507.2(HPS5):c.1249C>A(p.Leu417Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.109 in 1,613,356 control chromosomes in the GnomAD database, including 10,718 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.14 ( 1535 hom., cov: 32)

Exomes 𝑓: 0.11 ( 9183 hom. )

Consequence

HPS5
NM_181507.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 3.25

Publications

30 publications found

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 Gene-Disease associations (from GenCC):

Hermansky-Pudlak syndrome 5
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen
Hermansky-Pudlak syndrome without pulmonary fibrosis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

HPS5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0015209019).

BP6

Variant 11-18297633-G-T is Benign according to our data. Variant chr11-18297633-G-T is described in ClinVar as Benign. ClinVar VariationId is 163677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.181 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181507.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
HPS5	NM_181507.2	MANE Select	c.1249C>A	p.Leu417Met	missense	Exon 11 of 23	NP_852608.1
HPS5	NM_001440902.1		c.1249C>A	p.Leu417Met	missense	Exon 11 of 24	NP_001427831.1
HPS5	NM_001440903.1		c.1249C>A	p.Leu417Met	missense	Exon 11 of 24	NP_001427832.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
HPS5	ENST00000349215.8	TSL:1 MANE Select	c.1249C>A	p.Leu417Met	missense	Exon 11 of 23	ENSP00000265967.5
HPS5	ENST00000396253.7	TSL:1	c.907C>A	p.Leu303Met	missense	Exon 10 of 22	ENSP00000379552.3
HPS5	ENST00000438420.6	TSL:1	c.907C>A	p.Leu303Met	missense	Exon 10 of 22	ENSP00000399590.2

Frequencies

GnomAD3 genomes

AF:

0.137

AC:

20876

AN:

152092

Hom.:

1532

Cov.:

show subpopulations

Gnomad AFR

AF:

0.184

Gnomad AMI

AF:

0.0559

Gnomad AMR

AF:

0.154

Gnomad ASJ

AF:

0.123

Gnomad EAS

AF:

0.119

Gnomad SAS

AF:

0.130

Gnomad FIN

AF:

0.175

Gnomad MID

AF:

0.155

Gnomad NFE

AF:

0.102

Gnomad OTH

AF:

0.146

GnomAD2 exomes

AF:

0.136

AC:

34133

AN:

251352

AF XY:

0.131

show subpopulations

Gnomad AFR exome

AF:

0.184

Gnomad AMR exome

AF:

0.212

Gnomad ASJ exome

AF:

0.119

Gnomad EAS exome

AF:

0.119

Gnomad FIN exome

AF:

0.161

Gnomad NFE exome

AF:

0.108

Gnomad OTH exome

AF:

0.127

GnomAD4 exome

AF:

0.106

AC:

155104

AN:

1461144

Hom.:

9183

Cov.:

AF XY:

0.106

AC XY:

77401

AN XY:

726932

show subpopulations

African (AFR)

AF:

0.186

AC:

6214

AN:

33468

American (AMR)

AF:

0.204

AC:

9120

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.120

AC:

3140

AN:

26126

East Asian (EAS)

AF:

0.153

AC:

6071

AN:

39684

South Asian (SAS)

AF:

0.127

AC:

10944

AN:

86250

European-Finnish (FIN)

AF:

0.159

AC:

8502

AN:

53408

Middle Eastern (MID)

AF:

0.154

AC:

884

AN:

5756

European-Non Finnish (NFE)

AF:

0.0931

AC:

103472

AN:

1111360

Other (OTH)

AF:

0.112

AC:

6757

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

6632

13264

19896

26528

33160

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3810

7620

11430

15240

19050

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.137

AC:

20887

AN:

152212

Hom.:

1535

Cov.:

AF XY:

0.140

AC XY:

10447

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.184

AC:

7646

AN:

41524

American (AMR)

AF:

0.154

AC:

2362

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.123

AC:

428

AN:

3468

East Asian (EAS)

AF:

0.120

AC:

620

AN:

5188

South Asian (SAS)

AF:

0.129

AC:

624

AN:

4826

European-Finnish (FIN)

AF:

0.175

AC:

1852

AN:

10578

Middle Eastern (MID)

AF:

0.139

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.102

AC:

6958

AN:

68012

Other (OTH)

AF:

0.145

AC:

305

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

919

1839

2758

3678

4597

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

222

444

666

888

1110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.115

Hom.:

5279

Bravo

AF:

0.138

TwinsUK

AF:

0.0944

AC:

350

ALSPAC

AF:

0.0825

AC:

318

ESP6500AA

AF:

0.189

AC:

833

ESP6500EA

AF:

0.0988

AC:

848

ExAC

AF:

0.135

AC:

16378

Asia WGS

AF:

0.140

AC:

488

AN:

3478

EpiCase

AF:

0.110

EpiControl

AF:

0.117

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (2)

Hermansky-Pudlak syndrome 5 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.17

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.30

Eigen

Uncertain

0.29

Eigen_PC

Benign

0.16

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.74

MetaRNN

Benign

0.0015

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.5

PhyloP100

3.2

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-0.98

REVEL

Benign

0.23

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.027

Polyphen

1.0

Vest4

0.32

MPC

0.33

ClinPred

0.026

GERP RS

2.3

Varity_R

0.28

gMVP

0.46

Mutation Taster

=93/7

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over