Genetic Variant NM_022081.6:c.707-28T>C (chr22-26465579-A-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.491

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id 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 link	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 link	c.707-28T>C		intron_variant	Intron 9 of 13	1	NM_022081.6	ENSP00000381213.2		Q9NQG7-1

Frequencies

GnomAD3 genomes

AF:

0.839

AC:

127486

AN:

152012

Hom.:

54141

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.861

AC:

215418

AN:

250248

Hom.:

93880

AF XY:

0.873

AC XY:

118237

AN XY:

135420

show subpopulations

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 SAS exome

AF:

0.907

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.:

AF XY:

0.895

AC XY:

638781

AN XY:

713764

show subpopulations

Gnomad4 AFR exome

AF:

0.704

Gnomad4 AMR exome

AF:

0.687

Gnomad4 ASJ exome

AF:

0.874

Gnomad4 EAS exome

AF:

0.849

Gnomad4 SAS exome

AF:

0.913

Gnomad4 FIN exome

AF:

0.959

Gnomad4 NFE exome

AF:

0.904

Gnomad4 OTH exome

AF:

0.884

GnomAD4 genome

AF:

0.838

AC:

127548

AN:

152130

Hom.:

54152

Cov.:

AF XY:

0.839

AC XY:

62435

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.709

Gnomad4 AMR

AF:

0.758

Gnomad4 ASJ

AF:

0.877

Gnomad4 EAS

AF:

0.851

Gnomad4 SAS

AF:

0.903

Gnomad4 FIN

AF:

0.965

Gnomad4 NFE

AF:

0.908

Gnomad4 OTH

AF:

0.849

Alfa

AF:

0.879

Hom.:

11000

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

LINK: link

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

DANN

Benign

0.65

BranchPoint Hunter

3.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over