3-149162784-A-G

Variant summary

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

The NM_032383.5(HPS3):c.2387A>G(p.Gln796Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HPS3 NM_032383.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.96

Genes affected

HPS3 (HGNC:15597): (HPS3 biogenesis of lysosomal organelles complex 2 subunit 1) This gene encodes a protein containing a potential clathrin-binding motif, consensus dileucine signals, and tyrosine-based sorting signals for targeting to vesicles of lysosomal lineage. The encoded protein may play a role in organelle biogenesis associated with melanosomes, platelet dense granules, and lysosomes. Mutations in this gene are associated with Hermansky-Pudlak syndrome type 3. [provided by RefSeq, Apr 2015]

CP (HGNC:2295): (ceruloplasmin) The protein encoded by this gene is a metalloprotein that binds most of the copper in plasma and is involved in the peroxidation of Fe(II)transferrin to Fe(III) transferrin. Mutations in this gene cause aceruloplasminemia, which results in iron accumulation and tissue damage, and is associated with diabetes and neurologic abnormalities. Two transcript variants, one protein-coding and the other not protein-coding, have been found for this gene. [provided by RefSeq, Feb 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HPS3	NM_032383.5	c.2387A>G	p.Gln796Arg	missense_variant	13/17	ENST00000296051.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HPS3	ENST00000296051.7	c.2387A>G	p.Gln796Arg	missense_variant	13/17	1	NM_032383.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 21, 2020

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with HPS3-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamine with arginine at codon 796 of the HPS3 protein (p.Gln796Arg). The glutamine residue is moderately conserved and there is a small physicochemical difference between glutamine and arginine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.044	T
BayesDel_noAF	Benign	-0.30
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.30	T;T
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.78	T;T
M_CAP	Benign	0.064	D
MetaRNN	Uncertain	0.48	T;T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	2.0	M;.
MutationTaster	Benign	0.68	D;D
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.6	N;N
REVEL	Benign	0.20
Sift	Uncertain	0.016	D;D
Sift4G	Uncertain	0.0090	D;D
Polyphen		0.93	P;P
Vest4		0.54
MutPred		0.41		Gain of MoRF binding (P = 0.06);.;
MVP		0.78
MPC		0.55
ClinPred		0.83	D
GERP RS		4.7
Varity_R		0.17
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1724008890; hg19: chr3-148880571; COSMIC: COSV56056410; COSMIC: COSV56056410;