Genetic Variant NM_022081.6:c.1847-47A>G (chr22-26458014-T-C) – 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.1847-47A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.923 in 1,452,274 control chromosomes in the GnomAD database, including 620,982 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.88 ( 59883 hom., cov: 34)

Exomes 𝑓: 0.93 ( 561099 hom. )

Consequence

HPS4
NM_022081.6 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -3.17

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.95).

BP6

Variant 22-26458014-T-C is Benign according to our data. Variant chr22-26458014-T-C is described in ClinVar as [Benign]. Clinvar id is 261533.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.939 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPS4	NM_022081.6 link	c.1847-47A>G		intron_variant	Intron 12 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.1847-47A>G		intron_variant	Intron 12 of 13	1	NM_022081.6	ENSP00000381213.2		Q9NQG7-1

Frequencies

GnomAD3 genomes

AF:

0.883

AC:

134353

AN:

152148

Hom.:

59867

Cov.:

show subpopulations

Gnomad AFR

AF:

0.777

Gnomad AMI

AF:

0.841

Gnomad AMR

AF:

0.799

Gnomad ASJ

AF:

0.964

Gnomad EAS

AF:

0.852

Gnomad SAS

AF:

0.925

Gnomad FIN

AF:

0.989

Gnomad MID

AF:

0.934

Gnomad NFE

AF:

0.945

Gnomad OTH

AF:

0.891

GnomAD3 exomes

AF:

0.890

AC:

188797

AN:

212160

Hom.:

84958

AF XY:

0.902

AC XY:

104086

AN XY:

115422

show subpopulations

Gnomad AFR exome

AF:

0.770

Gnomad AMR exome

AF:

0.696

Gnomad ASJ exome

AF:

0.970

Gnomad EAS exome

AF:

0.853

Gnomad SAS exome

AF:

0.928

Gnomad FIN exome

AF:

0.986

Gnomad NFE exome

AF:

0.943

Gnomad OTH exome

AF:

0.915

GnomAD4 exome

AF:

0.927

AC:

1205646

AN:

1300008

Hom.:

561099

Cov.:

AF XY:

0.930

AC XY:

607118

AN XY:

653134

show subpopulations

Gnomad4 AFR exome

AF:

0.769

Gnomad4 AMR exome

AF:

0.711

Gnomad4 ASJ exome

AF:

0.968

Gnomad4 EAS exome

AF:

0.848

Gnomad4 SAS exome

AF:

0.934

Gnomad4 FIN exome

AF:

0.982

Gnomad4 NFE exome

AF:

0.941

Gnomad4 OTH exome

AF:

0.920

GnomAD4 genome

AF:

0.883

AC:

134420

AN:

152266

Hom.:

59883

Cov.:

AF XY:

0.883

AC XY:

65701

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.777

Gnomad4 AMR

AF:

0.799

Gnomad4 ASJ

AF:

0.964

Gnomad4 EAS

AF:

0.852

Gnomad4 SAS

AF:

0.925

Gnomad4 FIN

AF:

0.989

Gnomad4 NFE

AF:

0.945

Gnomad4 OTH

AF:

0.888

Alfa

AF:

0.921

Hom.:

12852

Bravo

AF:

0.862

Asia WGS

AF:

0.859

AC:

2989

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

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

- -

Apr 07, 2019

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.95

CADD

Benign

0.021

DANN

Benign

0.20

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