rs281865098

chr22-26472342-T-Cchr22-26472342-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_022081.6(HPS4):c.461A>G(p.His154Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000411 in 1,461,114 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: HPS4 NM_022081.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 3.88

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HPS4	NM_022081.6	c.461A>G	p.His154Arg	missense_variant	6/14	ENST00000398145.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HPS4	ENST00000398145.7	c.461A>G	p.His154Arg	missense_variant	6/14	1	NM_022081.6	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251362 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135872

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461114 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 726916

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000307 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hermansky-Pudlak syndrome 4 Pathogenic:1 Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2003	- -
Uncertain significance, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 24, 2023	The p.His154Arg variant in HPS4 has been reported in 3 individuals with Hermansky-Pudlak syndrome 4 (PMID: 12664304, 31898847), segregated with disease in 2 affected relatives from 2 families (PMID: 12664304, 31898847), and has been identified in 0.0009% (1/113688) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs281865098). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID#: 21678) and has been interpreted as pathogenic by OMIM. Of the 3 affected individuals, 1 of those was a homozygote, which increases the likelihood that the p.His154Arg variant is pathogenic (PMID: 31898847). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM3_supporting, PP1, PP3, PM2_supporting (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
Cadd	Pathogenic	34
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D;.;D;.
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.84	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.89	D;D;D;D
MetaSVM	Uncertain	0.72	D
MutationAssessor	Uncertain	2.8	M;.;M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-4.9	D;D;D;D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.022	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;.
Polyphen		1.0	D;D;D;.
Vest4		0.69
MutPred		0.78		Gain of MoRF binding (P = 0.0392);.;Gain of MoRF binding (P = 0.0392);Gain of MoRF binding (P = 0.0392);
MVP		0.95
MPC		0.33
ClinPred		0.99	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.68
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.93		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.93		Position offset: 1
DS_DL_spliceai		0.25		Position offset: -40

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs281865098; hg19: chr22-26868308;