Genetic Variant HPS4:c.*1245_*1246delCG (chr22-26451986-ACG-A) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_SupportingBS2

The NM_022081.6(HPS4):c.*1245_*1246delCG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0129 in 149,082 control chromosomes in the GnomAD database, including 19 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.014 ( 19 hom., cov: 0)

Exomes 𝑓: 0.0061 ( 0 hom. )

Consequence

HPS4
NM_022081.6 3_prime_UTR

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: -0.477

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 was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0136 (1830/134766) while in subpopulation EAS AF = 0.0209 (94/4504). AF 95% confidence interval is 0.0175. There are 19 homozygotes in GnomAd4. There are 871 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position FAILED quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAd4 at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPS4	NM_022081.6 link	c.1245_1246delCG		3_prime_UTR_variant	Exon 14 of 14	ENST00000398145.7	NP_071364.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HPS4	ENST00000398145 link	c.1245_1246delCG		3_prime_UTR_variant	Exon 14 of 14	1	NM_022081.6	ENSP00000381213.2		Q9NQG7-1

Frequencies

GnomAD3 genomes

AF:

0.0136

AC:

1829

AN:

134686

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0137

Gnomad ASJ

AF:

0.0173

Gnomad EAS

AF:

0.0206

Gnomad SAS

AF:

0.00664

Gnomad FIN

AF:

0.0109

Gnomad MID

AF:

0.0101

Gnomad NFE

AF:

0.0145

Gnomad OTH

AF:

0.0182

GnomAD4 exome

AF:

0.00608

AC:

AN:

14316

Hom.:

AF XY:

0.00618

AC XY:

AN XY:

8096

show subpopulations

Gnomad4 AFR exome

AF:

0.0187

AC:

AN:

320

Gnomad4 AMR exome

AF:

0.00742

AC:

AN:

944

Gnomad4 ASJ exome

AF:

0.00949

AC:

AN:

316

Gnomad4 EAS exome

AF:

0.0132

AC:

AN:

304

Gnomad4 SAS exome

AF:

0.00455

AC:

AN:

2416

Gnomad4 FIN exome

AF:

0.00431

AC:

AN:

464

Gnomad4 NFE exome

AF:

0.00570

AC:

AN:

8948

Gnomad4 Remaining exome

AF:

0.00536

AC:

AN:

560

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0136

AC:

1830

AN:

134766

Hom.:

Cov.:

AF XY:

0.0134

AC XY:

871

AN XY:

65068

show subpopulations

Gnomad4 AFR

AF:

0.0121

AC:

0.0121029

AN:

0.0121029

Gnomad4 AMR

AF:

0.0137

AC:

0.0137118

AN:

0.0137118

Gnomad4 ASJ

AF:

0.0173

AC:

0.0172518

AN:

0.0172518

Gnomad4 EAS

AF:

0.0209

AC:

0.0208703

AN:

0.0208703

Gnomad4 SAS

AF:

0.00665

AC:

0.00664697

AN:

0.00664697

Gnomad4 FIN

AF:

0.0109

AC:

0.0108646

AN:

0.0108646

Gnomad4 NFE

AF:

0.0145

AC:

0.0144788

AN:

0.0144788

Gnomad4 OTH

AF:

0.0181

AC:

0.0180659

AN:

0.0180659

Heterozygous variant carriers

133

200

266

333

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00816

Hom.:

273

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hermansky-Pudlak syndrome

Uncertain:2

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Mutation Taster

=100/0

polymorphism

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