Genetic Variant NM_181507.2:c.2866T>C (chr11-18285431-A-G) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_181507.2(HPS5):c.2866T>C(p.Tyr956His) variant causes a missense change. The variant allele was found at a frequency of 0.000572 in 1,612,956 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00051 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00058 ( 4 hom. )

Consequence

HPS5
NM_181507.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: 7.13

Publications

8 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0141662955).

BP6

Variant 11-18285431-A-G is Benign according to our data. Variant chr11-18285431-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 435458.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000579 (845/1460626) while in subpopulation MID AF = 0.0128 (74/5762). AF 95% confidence interval is 0.0105. There are 4 homozygotes in GnomAdExome4. There are 438 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

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	UniProt
HPS5	NM_181507.2	MANE Select	c.2866T>C	p.Tyr956His	missense	Exon 20 of 23	NP_852608.1	Q9UPZ3-1
HPS5	NM_001440902.1		c.2866T>C	p.Tyr956His	missense	Exon 20 of 24	NP_001427831.1
HPS5	NM_001440903.1		c.2866T>C	p.Tyr956His	missense	Exon 20 of 24	NP_001427832.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HPS5	ENST00000349215.8	TSL:1 MANE Select	c.2866T>C	p.Tyr956His	missense	Exon 20 of 23	ENSP00000265967.5	Q9UPZ3-1
HPS5	ENST00000396253.7	TSL:1	c.2524T>C	p.Tyr842His	missense	Exon 19 of 22	ENSP00000379552.3	Q9UPZ3-2
HPS5	ENST00000438420.6	TSL:1	c.2524T>C	p.Tyr842His	missense	Exon 19 of 22	ENSP00000399590.2	Q9UPZ3-2

Frequencies

GnomAD3 genomes

AF:

0.000512

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00634

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000617

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000769

AC:

193

AN:

251102

AF XY:

0.000773

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000984

Gnomad ASJ exome

AF:

0.00586

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000801

Gnomad OTH exome

AF:

0.000491

GnomAD4 exome

AF:

0.000579

AC:

845

AN:

1460626

Hom.:

Cov.:

AF XY:

0.000603

AC XY:

438

AN XY:

726694

show subpopulations

African (AFR)

AF:

0.000179

AC:

AN:

33454

American (AMR)

AF:

0.000962

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00528

AC:

138

AN:

26116

East Asian (EAS)

AF:

0.00

AC:

AN:

39620

South Asian (SAS)

AF:

0.000487

AC:

AN:

86236

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53348

Middle Eastern (MID)

AF:

0.0128

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.000435

AC:

483

AN:

1111018

Other (OTH)

AF:

0.000978

AC:

AN:

60352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

128

171

214

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000512

AC:

AN:

152330

Hom.:

Cov.:

AF XY:

0.000510

AC XY:

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.0000962

AC:

AN:

41580

American (AMR)

AF:

0.000458

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00634

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000617

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000905

Hom.:

Bravo

AF:

0.000627

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.000725

AC:

EpiCase

AF:

0.00120

EpiControl

AF:

0.00178

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Hermansky-Pudlak syndrome 5 (1)

HPS5-related disorder (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.47

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Uncertain

-0.050

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.16

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.017

MetaRNN

Benign

0.014

MetaSVM

Benign

-0.49

MutationAssessor

Uncertain

2.5

PhyloP100

7.1

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-1.4

REVEL

Uncertain

0.31

Sift

Benign

0.13

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.68

MVP

0.73

MPC

0.38

ClinPred

0.063

GERP RS

5.8

Varity_R

0.23

gMVP

0.62

Mutation Taster

=71/29

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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