rs3747129

chr22-26466075-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_022081.6(HPS4):c.706+151C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.156 in 1,567,474 control chromosomes in the GnomAD database, including 22,302 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.12 (1643 hom., cov: 32)
  • Exomes 𝑓: 0.16 (20659 hom.)
• Consequence: HPS4 NM_022081.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0160

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_addAF=-0.833905).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.345 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HPS4	NM_022081.6	c.706+151C>T		intron_variant		ENST00000398145.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HPS4	ENST00000398145.7	c.706+151C>T		intron_variant		1	NM_022081.6	P2

Frequencies

GnomAD3 genomes AF: 0.124 AC: 18821 AN: 152036 Hom.: 1638 Cov.: 32

Gnomad AFR AF: 0.0278

Gnomad AMI AF: 0.134

Gnomad AMR AF: 0.115

Gnomad ASJ AF: 0.147

Gnomad EAS AF: 0.236

Gnomad SAS AF: 0.359

Gnomad FIN AF: 0.197

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.146

Gnomad OTH AF: 0.131

GnomAD3 exomes AF: 0.173 AC: 33094 AN: 191268 Hom.: 3600 AF XY: 0.188 AC XY: 19282 AN XY: 102368

Gnomad AFR exome AF: 0.0243

Gnomad AMR exome AF: 0.101

Gnomad ASJ exome AF: 0.158

Gnomad EAS exome AF: 0.227

Gnomad SAS exome AF: 0.362

Gnomad FIN exome AF: 0.193

Gnomad NFE exome AF: 0.151

Gnomad OTH exome AF: 0.165

GnomAD4 exome AF: 0.160 AC: 226005 AN: 1415320 Hom.: 20659 Cov.: 31 AF XY: 0.167 AC XY: 116803 AN XY: 701058

Gnomad4 AFR exome AF: 0.0246

Gnomad4 AMR exome AF: 0.108

Gnomad4 ASJ exome AF: 0.154

Gnomad4 EAS exome AF: 0.226

Gnomad4 SAS exome AF: 0.359

Gnomad4 FIN exome AF: 0.191

Gnomad4 NFE exome AF: 0.147

Gnomad4 OTH exome AF: 0.163

GnomAD4 genome AF: 0.124 AC: 18837 AN: 152154 Hom.: 1643 Cov.: 32 AF XY: 0.130 AC XY: 9690 AN XY: 74364

Gnomad4 AFR AF: 0.0277

Gnomad4 AMR AF: 0.115

Gnomad4 ASJ AF: 0.147

Gnomad4 EAS AF: 0.236

Gnomad4 SAS AF: 0.359

Gnomad4 FIN AF: 0.197

Gnomad4 NFE AF: 0.146

Gnomad4 OTH AF: 0.138

Alfa AF: 0.151 Hom.: 3732

Bravo AF: 0.111

TwinsUK AF: 0.139 AC: 515

ALSPAC AF: 0.155 AC: 596

ExAC AF: 0.152 AC: 18017

Asia WGS AF: 0.268 AC: 932 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-0.83
Cadd	Benign	6.1
Dann	Uncertain	0.99
Eigen	Benign	-0.92
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.057	N
MutationTaster	Benign	7.9e-18	P;P;P;P
GERP RS		2.1

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: rs3747129; hg19: chr22-26862041; COSMIC: COSV61102632; COSMIC: COSV61102632;