rs727505003

Positions:

• chr10-98434018-G-A
• chr10-98434018-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000195.5(HPS1):​c.472C>T​(p.Arg158Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000385 in 1,558,516 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R158H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: HPS1 NM_000195.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 3.63

Genes affected

HPS1 (HGNC:5163): (HPS1 biogenesis of lysosomal organelles complex 3 subunit 1) This gene encodes a protein that may play a role in organelle biogenesis associated with melanosomes, platelet dense granules, and lysosomes. The encoded protein is a component of three different protein complexes termed biogenesis of lysosome-related organelles complex (BLOC)-3, BLOC4, and BLOC5. Mutations in this gene are associated with Hermansky-Pudlak syndrome type 1. Alternative splicing results in multiple transcript variants. A pseudogene related to this gene is located on chromosome 22. [provided by RefSeq, Aug 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23036107).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HPS1	NM_000195.5	c.472C>T	p.Arg158Cys	missense_variant	6/20	ENST00000361490.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HPS1	ENST00000361490.9	c.472C>T	p.Arg158Cys	missense_variant	6/20	1	NM_000195.5	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000600 AC: 1 AN: 166642 Hom.: 0 AF XY: 0.0000113 AC XY: 1 AN XY: 88396

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000391

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000356 AC: 5 AN: 1406310 Hom.: 0 Cov.: 33 AF XY: 0.00000432 AC XY: 3 AN XY: 694380

Gnomad4 AFR exome AF: 0.0000311

Gnomad4 AMR exome AF: 0.0000273

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: 0.00000277

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152206 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74356

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 14, 2014

The Arg158Cys variant in HPS1 has not been reported in individuals with pulmonar y disease and data from large population studies is insufficient to assess the f requency of this variant. Computational prediction tools and conservation analys es suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, additional info rmation is needed to fully assess the clinical significance of the Arg158Cys var iant. -

Hermansky-Pudlak syndrome Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

May 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.39	T;T;T;.
Eigen	Benign	0.049
Eigen_PC	Benign	0.14
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.23	T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.5	L;L;L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.26	T
PROVEAN	Uncertain	-3.4	D;D;.;D
REVEL	Benign	0.047
Sift	Benign	0.079	T;T;.;T
Sift4G	Benign	0.15	T;T;T;T
Polyphen		0.027	B;B;B;D
Vest4		0.33
MutPred		0.42		Gain of catalytic residue at L159 (P = 0.0127);Gain of catalytic residue at L159 (P = 0.0127);Gain of catalytic residue at L159 (P = 0.0127);Gain of catalytic residue at L159 (P = 0.0127);
MVP		0.42
MPC		0.71
ClinPred		0.96	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs727505003; hg19: chr10-100193775;