Genetic Variant ENST00000396253.7:c.3G>A (chr11-18310873-C-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PVS1_ModerateBP6_Very_StrongBS1BS2

The ENST00000396253.7(HPS5):c.3G>A(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00412 in 1,612,654 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0030 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0042 ( 21 hom. )

Consequence

HPS5
ENST00000396253.7 start_lost

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts U:1B:10

Conservation

PhyloP100: 3.84

Publications

11 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, ClinGen, Labcorp Genetics (formerly Invitae)
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 -14 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 3 pathogenic variants. Next in-frame start position is after 52 codons. Genomic position: 18309061. Lost 0.051 part of the original CDS.

BP6

Variant 11-18310873-C-T is Benign according to our data. Variant chr11-18310873-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 197894.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.003 (454/151088) while in subpopulation NFE AF = 0.00489 (331/67646). AF 95% confidence interval is 0.00446. There are 1 homozygotes in GnomAd4. There are 217 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 21 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000396253.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HPS5	NM_181507.2	MANE Select	c.345G>A	p.Met115Ile	missense	Exon 5 of 23	NP_852608.1	Q9UPZ3-1
HPS5	NM_001440920.1		c.3G>A	p.Met1?	start_lost	Exon 4 of 23	NP_001427849.1
HPS5	NM_001440921.1		c.3G>A	p.Met1?	start_lost	Exon 4 of 23	NP_001427850.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HPS5	ENST00000396253.7	TSL:1	c.3G>A	p.Met1?	start_lost	Exon 4 of 22	ENSP00000379552.3	Q9UPZ3-2
HPS5	ENST00000438420.6	TSL:1	c.3G>A	p.Met1?	start_lost	Exon 4 of 22	ENSP00000399590.2	Q9UPZ3-2
HPS5	ENST00000349215.8	TSL:1 MANE Select	c.345G>A	p.Met115Ile	missense	Exon 5 of 23	ENSP00000265967.5	Q9UPZ3-1

Frequencies

GnomAD3 genomes

AF:

0.00301

AC:

454

AN:

150966

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00105

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00191

Gnomad ASJ

AF:

0.000290

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00190

Gnomad FIN

AF:

0.00294

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00489

Gnomad OTH

AF:

0.00485

GnomAD2 exomes

AF:

0.00285

AC:

715

AN:

251206

AF XY:

0.00277

show subpopulations

Gnomad AFR exome

AF:

0.000800

Gnomad AMR exome

AF:

0.00104

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00287

Gnomad NFE exome

AF:

0.00471

Gnomad OTH exome

AF:

0.00343

GnomAD4 exome

AF:

0.00424

AC:

6197

AN:

1461566

Hom.:

Cov.:

AF XY:

0.00417

AC XY:

3032

AN XY:

727114

show subpopulations

African (AFR)

AF:

0.000687

AC:

AN:

33474

American (AMR)

AF:

0.00134

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0000765

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00168

AC:

145

AN:

86248

European-Finnish (FIN)

AF:

0.00283

AC:

151

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00508

AC:

5649

AN:

1111730

Other (OTH)

AF:

0.00277

AC:

167

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

291

582

874

1165

1456

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

202

404

606

808

1010

<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:

0.00300

AC:

454

AN:

151088

Hom.:

Cov.:

AF XY:

0.00294

AC XY:

217

AN XY:

73856

show subpopulations

African (AFR)

AF:

0.00104

AC:

AN:

41218

American (AMR)

AF:

0.00191

AC:

AN:

15196

Ashkenazi Jewish (ASJ)

AF:

0.000290

AC:

AN:

3444

East Asian (EAS)

AF:

0.00

AC:

AN:

5060

South Asian (SAS)

AF:

0.00190

AC:

AN:

4742

European-Finnish (FIN)

AF:

0.00294

AC:

AN:

10536

Middle Eastern (MID)

AF:

0.00

AC:

AN:

262

European-Non Finnish (NFE)

AF:

0.00489

AC:

331

AN:

67646

Other (OTH)

AF:

0.00480

AC:

AN:

2082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

119

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00405

Hom.:

Bravo

AF:

0.00298

TwinsUK

AF:

0.00593

AC:

ALSPAC

AF:

0.00856

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00396

AC:

ExAC

AF:

0.00281

AC:

341

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00414

EpiControl

AF:

0.00415

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Hermansky-Pudlak syndrome 5 (2)

not specified (2)

HPS5-related disorder (1)

Inborn genetic diseases (1)

Thrombocytopenia;C1458140:Abnormal bleeding (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.067

Eigen

Benign

-0.92

Eigen_PC

Benign

-0.62

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.54

M_CAP

Benign

0.0051

MetaRNN

Benign

0.0092

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-2.1

PhyloP100

3.8

PrimateAI

Benign

0.42

PROVEAN

Benign

0.90

REVEL

Benign

0.057

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.24

MutPred

0.31

Gain of methylation at K111 (P = 0.1407)

MVP

0.35

MPC

0.056

ClinPred

0.0087

GERP RS

3.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.032

gMVP

0.081

Mutation Taster

=123/77

disease causing (ClinVar)

(source)

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

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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