22-26465579-A-G

Variant names:

• chr22-26465579-A-G
• rs3213583
• NM_022081.6:c.707-28T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_022081.6(HPS4):​c.707-28T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.887 in 1,582,382 control chromosomes in the GnomAD database, including 625,664 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.84 (54152 hom., cov: 31)
  • Exomes 𝑓: 0.89 (571512 hom.)
• Consequence: HPS4 NM_022081.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.491
• Publications: 9 publications found

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 Gene-Disease associations (from GenCC):

• Hermansky-Pudlak syndrome 4

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Hermansky-Pudlak syndrome with pulmonary fibrosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 3 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 22-26465579-A-G is Benign according to our data. Variant chr22-26465579-A-G is described in ClinVar as Benign. ClinVar VariationId is 261538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.902 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPS4	NM_022081.6	c.707-28T>C		intron_variant	Intron 9 of 13	ENST00000398145.7	NP_071364.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HPS4	ENST00000398145.7	c.707-28T>C		intron_variant	Intron 9 of 13	1	NM_022081.6	ENSP00000381213.2

Frequencies

GnomAD3 genomes AF: 0.839 AC: 127486 AN: 152012 Hom.: 54141 Cov.: 31

Gnomad AFR AF: 0.709

Gnomad AMI AF: 0.832

Gnomad AMR AF: 0.758

Gnomad ASJ AF: 0.877

Gnomad EAS AF: 0.851

Gnomad SAS AF: 0.903

Gnomad FIN AF: 0.965

Gnomad MID AF: 0.908

Gnomad NFE AF: 0.908

Gnomad OTH AF: 0.853

GnomAD2 exomes AF: 0.861 AC: 215418 AN: 250248 AF XY: 0.873

Gnomad AFR exome AF: 0.705

Gnomad AMR exome AF: 0.673

Gnomad ASJ exome AF: 0.877

Gnomad EAS exome AF: 0.854

Gnomad FIN exome AF: 0.964

Gnomad NFE exome AF: 0.907

Gnomad OTH exome AF: 0.882

GnomAD4 exome AF: 0.892 AC: 1276076 AN: 1430252 Hom.: 571512 Cov.: 24 AF XY: 0.895 AC XY: 638781 AN XY: 713764

African (AFR) AF: 0.704 AC: 23068 AN: 32788

American (AMR) AF: 0.687 AC: 30675 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.874 AC: 22668 AN: 25944

East Asian (EAS) AF: 0.849 AC: 33521 AN: 39482

South Asian (SAS) AF: 0.913 AC: 78145 AN: 85586

European-Finnish (FIN) AF: 0.959 AC: 50526 AN: 52672

Middle Eastern (MID) AF: 0.907 AC: 5159 AN: 5686

European-Non Finnish (NFE) AF: 0.904 AC: 979786 AN: 1084034

Other (OTH) AF: 0.884 AC: 52528 AN: 59394

GnomAD4 genome AF: 0.838 AC: 127548 AN: 152130 Hom.: 54152 Cov.: 31 AF XY: 0.839 AC XY: 62435 AN XY: 74374

African (AFR) AF: 0.709 AC: 29379 AN: 41454

American (AMR) AF: 0.758 AC: 11573 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.877 AC: 3046 AN: 3472

East Asian (EAS) AF: 0.851 AC: 4384 AN: 5154

South Asian (SAS) AF: 0.903 AC: 4361 AN: 4828

European-Finnish (FIN) AF: 0.965 AC: 10233 AN: 10606

Middle Eastern (MID) AF: 0.905 AC: 266 AN: 294

European-Non Finnish (NFE) AF: 0.908 AC: 61755 AN: 68028

Other (OTH) AF: 0.849 AC: 1794 AN: 2112

Alfa AF: 0.875 Hom.: 11204

Bravo AF: 0.815

Asia WGS AF: 0.844 AC: 2936 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hermansky-Pudlak syndrome 4 Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	12
DANN	Benign	0.65
PhyloP100		0.49
BranchPoint Hunter		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3213583; hg19: chr22-26861545; COSMIC: COSV61105165; COSMIC: COSV61105165;