rs189953957

chr22-26453436-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_022081.6(HPS4):c.1956-32T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.01 in 1,611,714 control chromosomes in the GnomAD database, including 110 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0074 (8 hom., cov: 32)
  • Exomes 𝑓: 0.010 (102 hom.)
• Consequence: HPS4 NM_022081.6 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -4.33

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 22-26453436-A-G is Benign according to our data. Variant chr22-26453436-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 261534.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00735 (1120/152338) while in subpopulation NFE AF= 0.0112 (760/68036). AF 95% confidence interval is 0.0105. There are 8 homozygotes in gnomad4. There are 571 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HPS4	NM_022081.6	c.1956-32T>C		intron_variant		ENST00000398145.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HPS4	ENST00000398145.7	c.1956-32T>C		intron_variant		1	NM_022081.6	P2

Frequencies

GnomAD3 genomes AF: 0.00735 AC: 1119 AN: 152220 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00159

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00648

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.0128

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0112

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00811 AC: 2039 AN: 251356 Hom.: 11 AF XY: 0.00838 AC XY: 1138 AN XY: 135860

Gnomad AFR exome AF: 0.00197

Gnomad AMR exome AF: 0.00324

Gnomad ASJ exome AF: 0.00615

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00545

Gnomad FIN exome AF: 0.0120

Gnomad NFE exome AF: 0.0119

Gnomad OTH exome AF: 0.00783

GnomAD4 exome AF: 0.0103 AC: 15057 AN: 1459376 Hom.: 102 Cov.: 30 AF XY: 0.0102 AC XY: 7427 AN XY: 726122

Gnomad4 AFR exome AF: 0.00177

Gnomad4 AMR exome AF: 0.00364

Gnomad4 ASJ exome AF: 0.00693

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00556

Gnomad4 FIN exome AF: 0.0115

Gnomad4 NFE exome AF: 0.0117

Gnomad4 OTH exome AF: 0.00893

GnomAD4 genome AF: 0.00735 AC: 1120 AN: 152338 Hom.: 8 Cov.: 32 AF XY: 0.00766 AC XY: 571 AN XY: 74496

Gnomad4 AFR AF: 0.00159

Gnomad4 AMR AF: 0.00647

Gnomad4 ASJ AF: 0.00749

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00435

Gnomad4 FIN AF: 0.0128

Gnomad4 NFE AF: 0.0112

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00771 Hom.: 1

Bravo AF: 0.00699

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	0.0010
Dann	Benign	0.23

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: rs189953957; hg19: chr22-26849402;