rs281865090

Positions:

• chr10-98417664-A-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000195.5(HPS1):​c.2003T>C​(p.Leu668Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,592 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: HPS1 NM_000195.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 8.90

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 Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant 10-98417664-A-G is Pathogenic according to our data. Variant chr10-98417664-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1499624.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HPS1	NM_000195.5	c.2003T>C	p.Leu668Pro	missense_variant	20/20	ENST00000361490.9	NP_000186.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HPS1	ENST00000361490.9	c.2003T>C	p.Leu668Pro	missense_variant	20/20	1	NM_000195.5	ENSP00000355310	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461592 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727112

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hermansky-Pudlak syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 25, 2024

Variant summary: HPS1 c.2003T>C (p.Leu668Pro) results in a non-conservative amino acid change located in the FUZ/MON1/HPS1, third Longin domain (IPR043970) of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 248842 control chromosomes (gnomAD). c.2003T>C has been reported in the literature in multiple individuals affected with Hermansky-Pudlak Syndrome (e.g. Ito_2005, Kanazu_2014, Wei_2016). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, indicating that the variant results in instability of the protein (Ito_2005). The following publications have been ascertained in the context of this evaluation (PMID: 16185271, 25400188, 27593200). ClinVar contains an entry for this variant (Variation ID: 1499624). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 26, 2022

This missense change has been observed in individual(s) with clinical features of Hermansky-Pudlak syndrome (PMID: 16185271, 25400188, 27593200, 31141302, 32725903). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects HPS1 function (PMID: 16185271). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt HPS1 protein function. ClinVar contains an entry for this variant (Variation ID: 1499624). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 668 of the HPS1 protein (p.Leu668Pro). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.58	D;D;D
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	.;.;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Uncertain	2.5	M;M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.9	D;D;.
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0030	D;D;.
Sift4G	Pathogenic	0.0010	D;D;D
Vest4		0.96
MutPred		0.91		Loss of helix (P = 0.0104);Loss of helix (P = 0.0104);Loss of helix (P = 0.0104);
MVP		0.93
MPC		0.80
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.87
gMVP		0.92

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: rs281865090; hg19: chr10-100177421;