dbSNP rs149830675: HPS4:p.Ile84Leu (chr22-26477019-T-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_022081.6(HPS4):c.250A>T(p.Ile84Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I84V) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

HPS4
NM_022081.6 missense

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: -2.99

Publications

0 publications found

Variant links:

Genes affected

HPS4 (HGNC:15844): (HPS4 biogenesis of lysosomal organelles complex 3 subunit 2) This gene encodes a protein component of biogenesis of lysosome-related organelles complexes (BLOC). BLOC complexes are important for the formation of endosomal-lysosomal organelles such as melanosomes and platelet dense granules. Mutations in this gene result in subtype 4 of Hermansky-Pudlak syndrome, a form of albinism. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2012]

HPS4 Gene-Disease associations (from GenCC):

Hermansky-Pudlak syndrome 4
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P, Ambry Genetics
Hermansky-Pudlak syndrome with pulmonary fibrosis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

HPS4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08887276).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022081.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HPS4	NM_022081.6	MANE Select	c.250A>T	p.Ile84Leu	missense	Exon 4 of 14	NP_071364.4
HPS4	NM_001349900.2		c.250A>T	p.Ile84Leu	missense	Exon 4 of 15	NP_001336829.1	F1LLU8
HPS4	NM_001349901.1		c.250A>T	p.Ile84Leu	missense	Exon 4 of 15	NP_001336830.1	F1LLU8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HPS4	ENST00000398145.7	TSL:1 MANE Select	c.250A>T	p.Ile84Leu	missense	Exon 4 of 14	ENSP00000381213.2	Q9NQG7-1
HPS4	ENST00000402105.7	TSL:1	c.235A>T	p.Ile79Leu	missense	Exon 2 of 12	ENSP00000384185.3	Q9NQG7-3
HPS4	ENST00000439453.5	TSL:1	n.250A>T		non_coding_transcript_exon	Exon 4 of 14	ENSP00000406764.1	F8WC53

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.011

BayesDel_noAF

Benign

-0.25

CADD

Benign

0.0010

(source)

DANN

Benign

0.73

DEOGEN2

Benign

0.10

Eigen

Benign

-1.9

Eigen_PC

Benign

-2.1

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.59

M_CAP

Uncertain

0.086

MetaRNN

Benign

0.089

MetaSVM

Benign

-0.84

MutationAssessor

Uncertain

2.0

PhyloP100

-3.0

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.5

REVEL

Benign

0.27

Sift

Benign

0.41

Sift4G

Benign

0.089

Polyphen

0.021

Vest4

0.32

MutPred

0.35

Gain of helix (P = 0.0854)

MVP

0.58

MPC

0.13

ClinPred

0.051

GERP RS

-11

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.049

gMVP

0.50

Mutation Taster

=97/3

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over