22-26458475-G-C

Variant names:

• chr22-26458475-G-C
• rs1894706
• NM_022081.6:c.1816C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_022081.6(HPS4):​c.1816C>G​(p.His606Asp) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H606Y) has been classified as Benign.

• Frequency: Genomes: not found (cov: 30)
• Consequence: HPS4 NM_022081.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.06
• Publications: 40 publications found

Genes affected

HPS4 (HGNC:15844): (HPS4 biogenesis of lysosomal organelles complex 3 subunit 2) This gene encodes a protein component of biogenesis of lysosome-related organelles complexes (BLOC). BLOC complexes are important for the formation of endosomal-lysosomal organelles such as melanosomes and platelet dense granules. Mutations in this gene result in subtype 4 of Hermansky-Pudlak syndrome, a form of albinism. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2012]

HPS4 Gene-Disease associations (from GenCC):

• Hermansky-Pudlak syndrome 4

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Hermansky-Pudlak syndrome with pulmonary fibrosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.931

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPS4	NM_022081.6	c.1816C>G	p.His606Asp	missense_variant	Exon 12 of 14	ENST00000398145.7	NP_071364.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HPS4	ENST00000398145.7	c.1816C>G	p.His606Asp	missense_variant	Exon 12 of 14	1	NM_022081.6	ENSP00000381213.2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 61

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 240681

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Uncertain	0.091	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.72	D;.;D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.82	.;T;T
M_CAP	Benign	0.037	D
MetaRNN	Pathogenic	0.93	D;D;D
MetaSVM	Benign	-0.78	T
MutationAssessor	Uncertain	2.6	M;.;M
PhyloP100		8.1
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-6.2	D;D;D
REVEL	Uncertain	0.40
Sift	Uncertain	0.010	D;D;D
Sift4G	Uncertain	0.0090	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.86
MutPred		0.49		Gain of loop (P = 0.069);.;Gain of loop (P = 0.069);
MVP		0.46
MPC		0.34
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.48
gMVP		0.82
Mutation Taster		=41/59	disease causing

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

Other links and lift over

dbSNP: rs1894706; hg19: chr22-26854441;