rs281865102

chr11-18292011-A-Cchr11-18292011-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_181507.2(HPS5):c.1871T>G(p.Leu624Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,242 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L624P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HPS5 NM_181507.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.05

Genes affected

HPS5 (HGNC:17022): (HPS5 biogenesis of lysosomal organelles complex 2 subunit 2) This gene encodes a protein that may play a role in organelle biogenesis associated with melanosomes, platelet dense granules, and lysosomes. This protein interacts with Hermansky-Pudlak syndrome 6 protein and may interact with the cytoplasmic domain of integrin, alpha-3. Mutations in this gene are associated with Hermansky-Pudlak syndrome type 5. Multiple transcript variants encoding two distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.906
• PP5: Variant 11-18292011-A-C is Pathogenic according to our data. Variant chr11-18292011-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2735561.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-18292011-A-C is described in UniProt as null. Variant chr11-18292011-A-C is described in UniProt as null. Variant chr11-18292011-A-C is described in Lovd as [Pathogenic]. Variant chr11-18292011-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HPS5	NM_181507.2	c.1871T>G	p.Leu624Arg	missense_variant	16/23	ENST00000349215.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HPS5	ENST00000349215.8	c.1871T>G	p.Leu624Arg	missense_variant	16/23	1	NM_181507.2	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461242 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726956

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 04, 2024

This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 624 of the HPS5 protein (p.Leu624Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Hermansky–Pudlak syndrome (PMID: 15296495, 28640947). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.91	D;D;D
MetaSVM	Uncertain	0.22	D
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-2.2	N;N;N
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.86
MutPred		0.73		.;Gain of solvent accessibility (P = 0.0171);.;
MVP		0.97
MPC		0.38
ClinPred		0.98	D
GERP RS		5.7
Varity_R		0.55
gMVP		0.67

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: rs281865102; hg19: chr11-18313558;