Genetic Variant NM_022081.6:c.1715A>G (chr22-26458576-T-C) – 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_022081.6(HPS4):c.1715A>G(p.Tyr572Cys) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Consequence

HPS4
NM_022081.6 missense, splice_region

Scores

Splicing: ADA: 0.003999

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.72

Publications

1 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: G2P, ClinGen, Labcorp Genetics (formerly Invitae), 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 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.808

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
HPS4	NM_022081.6	MANE Select	c.1715A>G	p.Tyr572Cys	missense splice_region	Exon 12 of 14	NP_071364.4
HPS4	NM_001349900.2		c.1769A>G	p.Tyr590Cys	missense splice_region	Exon 13 of 15	NP_001336829.1
HPS4	NM_001349901.1		c.1769A>G	p.Tyr590Cys	missense splice_region	Exon 13 of 15	NP_001336830.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
HPS4	ENST00000398145.7	TSL:1 MANE Select	c.1715A>G	p.Tyr572Cys	missense splice_region	Exon 12 of 14	ENSP00000381213.2
HPS4	ENST00000402105.7	TSL:1	c.1700A>G	p.Tyr567Cys	missense splice_region	Exon 10 of 12	ENSP00000384185.3
HPS4	ENST00000439453.5	TSL:1	n.*1233A>G		splice_region non_coding_transcript_exon	Exon 12 of 14	ENSP00000406764.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Uncertain

0.10

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.72

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.026

MetaRNN

Pathogenic

0.81

MetaSVM

Benign

-0.94

MutationAssessor

Uncertain

2.6

PhyloP100

3.7

PrimateAI

Uncertain

0.79

PROVEAN

Pathogenic

-6.4

REVEL

Uncertain

0.35

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0040

Polyphen

1.0

Vest4

0.77

MutPred

0.50

Loss of phosphorylation at Y572 (P = 0.0733)

MVP

0.39

MPC

0.33

ClinPred

0.99

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.40

gMVP

0.67

Mutation Taster

=67/33

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0040

dbscSNV1_RF

Benign

0.12

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