10-98429811-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000195.5(HPS1):c.847G>C(p.Gly283Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000335 in 1,613,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G283A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00052 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00032 (0 hom.)
• Consequence: HPS1 NM_000195.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: -1.55

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.009726554).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HPS1	NM_000195.5	c.847G>C	p.Gly283Arg	missense_variant	9/20	ENST00000361490.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HPS1	ENST00000361490.9	c.847G>C	p.Gly283Arg	missense_variant	9/20	1	NM_000195.5	P1

Frequencies

GnomAD3 genomes AF: 0.000519 AC: 79 AN: 152206 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00106

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000965

Gnomad SAS AF: 0.000413

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000386 AC: 97 AN: 251054 Hom.: 0 AF XY: 0.000405 AC XY: 55 AN XY: 135782

Gnomad AFR exome AF: 0.000801

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.000870

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000370

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000316 AC: 462 AN: 1461492 Hom.: 0 Cov.: 34 AF XY: 0.000320 AC XY: 233 AN XY: 727064

Gnomad4 AFR exome AF: 0.000956

Gnomad4 AMR exome AF: 0.000380

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.000403

Gnomad4 SAS exome AF: 0.000267

Gnomad4 FIN exome AF: 0.0000566

Gnomad4 NFE exome AF: 0.000311

Gnomad4 OTH exome AF: 0.000364

GnomAD4 genome AF: 0.000519 AC: 79 AN: 152324 Hom.: 0 Cov.: 33 AF XY: 0.000363 AC XY: 27 AN XY: 74470

Gnomad4 AFR AF: 0.00106

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000967

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000139 Hom.: 495

Bravo AF: 0.000491

ExAC AF: 0.000412 AC: 50

EpiCase AF: 0.000273

EpiControl AF: 0.000474

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 27, 2019	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Sep 30, 2022	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 283 of the HPS1 protein (p.Gly283Arg). This variant is present in population databases (rs11592273, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with HPS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1188296). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Hermansky-Pudlak syndrome Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Jan 24, 2020

- -

Hermansky-Pudlak syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 04, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.71
Cadd	Benign	0.0010
Dann	Benign	0.40
DEOGEN2	Benign	0.052	T;T;T;.
Eigen	Benign	-2.5
Eigen_PC	Benign	-2.5
FATHMM_MKL	Benign	0.047	N
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.0097	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.90	N;N;N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.020	N;N;.;N
REVEL	Benign	0.013
Sift	Benign	0.68	T;T;.;T
Sift4G	Benign	0.57	T;T;T;T
Polyphen		0.0020	B;B;B;B
Vest4		0.11
MVP		0.085
MPC		0.17
ClinPred		0.00098	T
GERP RS		-5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.030
gMVP		0.18

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

LitVar

Other links and lift over

dbSNP: rs11592273; hg19: chr10-100189568;