22-26466246-T-A

Variant names:

• chr22-26466246-T-A
• rs713998
• NM_022081.6:c.686A>T

Variant summary

Our verdict is Likely benign. The variant received -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. 15/22 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
• 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: Likely_benign. The variant received -2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022081.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPS4	NM_022081.6	MANE Select	c.686A>T	p.Glu229Val	missense	Exon 9 of 14	NP_071364.4
	HPS4	NM_001349900.2		c.686A>T	p.Glu229Val	missense	Exon 9 of 15	NP_001336829.1
	HPS4	NM_001349901.1		c.686A>T	p.Glu229Val	missense	Exon 9 of 15	NP_001336830.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPS4	ENST00000398145.7	TSL:1 MANE Select	c.686A>T	p.Glu229Val	missense	Exon 9 of 14	ENSP00000381213.2
	HPS4	ENST00000402105.7	TSL:1	c.671A>T	p.Glu224Val	missense	Exon 7 of 12	ENSP00000384185.3
	HPS4	ENST00000439453.5	TSL:1	n.*204A>T		non_coding_transcript_exon	Exon 9 of 14	ENSP00000406764.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 52

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.058	N
LIST_S2	Benign	0.39	T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.058	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	0.20	N
PhyloP100		0.17
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.24	N
REVEL	Uncertain	0.39
Sift	Benign	0.28	T
Sift4G	Benign	0.28	T
Polyphen		0.0	B
Vest4		0.11
MutPred		0.19		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
Mutation Taster		=99/1	polymorphism

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: rs713998; hg19: chr22-26862212;