chr11-18291663-A-G

Position:

• chr11-18291663-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_181507.2(HPS5):​c.2219T>C​(p.Leu740Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: HPS5 NM_181507.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.85

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]

HPS5 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.867
• PP5: Variant 11-18291663-A-G is Pathogenic according to our data. Variant chr11-18291663-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 427880.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-18291663-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HPS5	NM_181507.2	c.2219T>C	p.Leu740Ser	missense_variant	16/23	ENST00000349215.8	NP_852608.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HPS5	ENST00000349215.8	c.2219T>C	p.Leu740Ser	missense_variant	16/23	1	NM_181507.2	ENSP00000265967.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hermansky-Pudlak syndrome 5 Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Laboratoire de Génétique Moléculaire, CHU Bordeaux

Mar 14, 2017

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	.;T;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.78	.;T;T
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.87	D;D;D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Uncertain	2.7	.;M;.
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-2.5	N;D;N
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D;D;D
Sift4G	Benign	0.11	T;T;T
Polyphen		1.0	.;D;.
Vest4		0.85
MutPred		0.66		.;Loss of stability (P = 0.0245);.;
MVP		0.97
MPC		0.37
ClinPred		0.97	D
GERP RS		5.6
Varity_R		0.42
gMVP		0.75

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: rs1131692149; hg19: chr11-18313210;