rs797045615

chr22-26458576-T-Achr22-26458576-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_022081.6(HPS4):c.1715A>T(p.Tyr572Phe) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000684 in 1,461,832 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. Y572C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HPS4 NM_022081.6 missense, splice_region
• Scores: Splicing: ADA: 0.0005024
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.72

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20966399).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HPS4	NM_022081.6	c.1715A>T	p.Tyr572Phe	missense_variant, splice_region_variant	12/14	ENST00000398145.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HPS4	ENST00000398145.7	c.1715A>T	p.Tyr572Phe	missense_variant, splice_region_variant	12/14	1	NM_022081.6	P2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251330 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135850

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461832 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 727212

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	21
Dann	Benign	0.97
DEOGEN2	Benign	0.26	T;.;T
Eigen	Benign	-0.099
Eigen_PC	Benign	-0.024
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.21	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M;.;M
MutationTaster	Benign	0.53	D;D;D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-2.7	D;D;D
REVEL	Benign	0.094
Sift	Benign	0.041	D;D;D
Sift4G	Benign	0.099	T;T;T
Polyphen		0.10	B;B;B
Vest4		0.34
MutPred		0.51		Loss of phosphorylation at Y572 (P = 0.0733);.;Loss of phosphorylation at Y572 (P = 0.0733);
MVP		0.21
MPC		0.087
ClinPred		0.68	D
GERP RS		3.5
Varity_R		0.18
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00050
dbscSNV1_RF	Benign	0.082
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: rs797045615; hg19: chr22-26854542;