dbSNP rs113381494: HPS3:p.His384Gln (chr3-149145535-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_032383.5(HPS3):c.1152C>A(p.His384Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,442 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H384P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

HPS3
NM_032383.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.03

Publications

0 publications found

Variant links:

Genes affected

HPS3 (HGNC:15597): (HPS3 biogenesis of lysosomal organelles complex 2 subunit 1) This gene encodes a protein containing a potential clathrin-binding motif, consensus dileucine signals, and tyrosine-based sorting signals for targeting to vesicles of lysosomal lineage. The encoded protein may play a role in organelle biogenesis associated with melanosomes, platelet dense granules, and lysosomes. Mutations in this gene are associated with Hermansky-Pudlak syndrome type 3. [provided by RefSeq, Apr 2015]

HPS3 Gene-Disease associations (from GenCC):

Hermansky-Pudlak syndrome 3
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

HPS3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.81

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPS3	NM_032383.5 link	c.1152C>A	p.His384Gln	missense_variant	Exon 5 of 17	ENST00000296051.7	NP_115759.2	Q969F9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HPS3	ENST00000296051.7 link	c.1152C>A	p.His384Gln	missense_variant	Exon 5 of 17	1	NM_032383.5	ENSP00000296051.2	Q969F9-1
HPS3	ENST00000460120.5 link	c.657C>A	p.His219Gln	missense_variant	Exon 4 of 16	2		ENSP00000418230.1	G5E9V4
HPS3	ENST00000462030.5 link	n.1751C>A		non_coding_transcript_exon_variant	Exon 5 of 7	2
HPS3	ENST00000486530.1 link	n.1185C>A		non_coding_transcript_exon_variant	Exon 5 of 7	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461442

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727030

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39682

South Asian (SAS)

AF:

0.00

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111624

Other (OTH)

AF:

0.0000166

AC:

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.80

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.17

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.70

D;T

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.84

T;T

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.81

D;D

MetaSVM

Uncertain

-0.029

MutationAssessor

Benign

1.9

L;.

PhyloP100

-1.0

PrimateAI

Uncertain

0.76

PROVEAN

Pathogenic

-5.8

D;D

REVEL

Uncertain

0.62

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.0050

D;D

Polyphen

1.0

D;D

Vest4

0.96

MutPred

0.60

Loss of sheet (P = 0.0126);.;

MVP

0.76

MPC

0.13

ClinPred

0.99

GERP RS

-5.5

Varity_R

0.69

gMVP

0.83

Mutation Taster

=47/53

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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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rs113381494

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over