rs3747134

Positions:

• chr22-26482015-G-A
• chr22-26482015-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_022081.6(HPS4):​c.-253C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.854 in 513,228 control chromosomes in the GnomAD database, including 189,039 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.82 (51305 hom., cov: 33)
  • Exomes 𝑓: 0.87 (137734 hom.)
• Consequence: HPS4 NM_022081.6 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.340

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 22-26482015-G-A is Benign according to our data. Variant chr22-26482015-G-A is described in ClinVar as [Benign]. Clinvar id is 341028.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.883 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HPS4	NM_022081.6	c.-253C>T		5_prime_UTR_premature_start_codon_gain_variant	2/14	ENST00000398145.7	NP_071364.4
HPS4	NM_022081.6	c.-253C>T		5_prime_UTR_variant	2/14	ENST00000398145.7	NP_071364.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HPS4	ENST00000398145.7	c.-253C>T		5_prime_UTR_premature_start_codon_gain_variant	2/14	1	NM_022081.6	ENSP00000381213.2
HPS4	ENST00000398145.7	c.-253C>T		5_prime_UTR_variant	2/14	1	NM_022081.6	ENSP00000381213.2

Frequencies

GnomAD3 genomes AF: 0.815 AC: 123998 AN: 152056 Hom.: 51298 Cov.: 33

Gnomad AFR AF: 0.677

Gnomad AMI AF: 0.821

Gnomad AMR AF: 0.738

Gnomad ASJ AF: 0.852

Gnomad EAS AF: 0.786

Gnomad SAS AF: 0.891

Gnomad FIN AF: 0.958

Gnomad MID AF: 0.877

Gnomad NFE AF: 0.889

Gnomad OTH AF: 0.823

GnomAD4 exome AF: 0.871 AC: 314475 AN: 361052 Hom.: 137734 Cov.: 3 AF XY: 0.876 AC XY: 168117 AN XY: 191974

Gnomad4 AFR exome AF: 0.678

Gnomad4 AMR exome AF: 0.706

Gnomad4 ASJ exome AF: 0.853

Gnomad4 EAS exome AF: 0.769

Gnomad4 SAS exome AF: 0.907

Gnomad4 FIN exome AF: 0.945

Gnomad4 NFE exome AF: 0.890

Gnomad4 OTH exome AF: 0.861

GnomAD4 genome AF: 0.815 AC: 124053 AN: 152176 Hom.: 51305 Cov.: 33 AF XY: 0.817 AC XY: 60760 AN XY: 74402

Gnomad4 AFR AF: 0.677

Gnomad4 AMR AF: 0.738

Gnomad4 ASJ AF: 0.852

Gnomad4 EAS AF: 0.786

Gnomad4 SAS AF: 0.891

Gnomad4 FIN AF: 0.958

Gnomad4 NFE AF: 0.889

Gnomad4 OTH AF: 0.820

Alfa AF: 0.859 Hom.: 56549

Bravo AF: 0.789

Asia WGS AF: 0.807 AC: 2808 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

Hermansky-Pudlak syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	5.7
DANN	Benign	0.72

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: rs3747134; hg19: chr22-26877981;