chr22-26466246-T-A

Position:

• chr22-26466246-T-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_022081.6(HPS4):​c.686A>T​(p.Glu229Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign 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. E229G) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HPS4 NM_022081.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.170

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.057633787).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HPS4	NM_022081.6	c.686A>T	p.Glu229Val	missense_variant	9/14	ENST00000398145.7	NP_071364.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HPS4	ENST00000398145.7	c.686A>T	p.Glu229Val	missense_variant	9/14	1	NM_022081.6	ENSP00000381213.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 52

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.016	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	12
DANN	Benign	0.89
DEOGEN2	Benign	0.090	T;.;T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.058	N
LIST_S2	Benign	0.39	.;T;T;T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.058	T;T;T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	0.20	N;.;N;.
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.24	N;N;N;N
REVEL	Uncertain	0.39
Sift	Benign	0.28	T;T;T;T
Sift4G	Benign	0.28	T;T;T;.
Polyphen		0.0	B;B;B;.
Vest4		0.11
MutPred		0.19		Loss of disorder (P = 0.0804);.;Loss of disorder (P = 0.0804);Loss of disorder (P = 0.0804);
MVP		0.56
MPC		0.049
ClinPred		0.032	T
GERP RS		0.46
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.1
Varity_R		0.044
gMVP		0.45

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: rs713998; hg19: chr22-26862212;