22-26451620-G-T

Position:

• chr22-26451620-G-T

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.*1613C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.887 in 152,260 control chromosomes in the GnomAD database, including 60,489 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.89 (60468 hom., cov: 32)
  • Exomes 𝑓: 1.0 (21 hom.)
• Consequence: HPS4 NM_022081.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.09

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.03).
• BP6: Variant 22-26451620-G-T is Benign according to our data. Variant chr22-26451620-G-T is described in ClinVar as [Benign]. Clinvar id is 340965.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.945 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HPS4	NM_022081.6	c.*1613C>A		3_prime_UTR_variant	14/14	ENST00000398145.7	NP_071364.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HPS4	ENST00000398145.7	c.*1613C>A		3_prime_UTR_variant	14/14	1	NM_022081.6	ENSP00000381213	P2

Frequencies

GnomAD3 genomes AF: 0.887 AC: 134981 AN: 152100 Hom.: 60452 Cov.: 32

Gnomad AFR AF: 0.779

Gnomad AMI AF: 0.886

Gnomad AMR AF: 0.802

Gnomad ASJ AF: 0.980

Gnomad EAS AF: 0.852

Gnomad SAS AF: 0.925

Gnomad FIN AF: 0.991

Gnomad MID AF: 0.934

Gnomad NFE AF: 0.951

Gnomad OTH AF: 0.897

GnomAD4 exome AF: 1.00 AC: 42 AN: 42 Hom.: 21 Cov.: 0 AF XY: 1.00 AC XY: 34 AN XY: 34

Gnomad4 AMR exome AF: 1.00

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 1.00

Gnomad4 OTH exome AF: 1.00

GnomAD4 genome AF: 0.887 AC: 135048 AN: 152218 Hom.: 60468 Cov.: 32 AF XY: 0.886 AC XY: 65974 AN XY: 74428

Gnomad4 AFR AF: 0.779

Gnomad4 AMR AF: 0.801

Gnomad4 ASJ AF: 0.980

Gnomad4 EAS AF: 0.852

Gnomad4 SAS AF: 0.925

Gnomad4 FIN AF: 0.991

Gnomad4 NFE AF: 0.951

Gnomad4 OTH AF: 0.894

Alfa AF: 0.934 Hom.: 63613

Bravo AF: 0.867

Asia WGS AF: 0.859 AC: 2989 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hermansky-Pudlak syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.45
DANN	Benign	0.59

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: rs3752589; hg19: chr22-26847586;