Genetic Variant PPL:c.*825A>C (chr16-4882559-T-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_002705.5(PPL):c.*825A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.533 in 151,892 control chromosomes in the GnomAD database, including 23,657 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.53 ( 23655 hom., cov: 31)

Exomes 𝑓: 0.16 ( 2 hom. )

Consequence

PPL
NM_002705.5 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.469

Publications

16 publications found

Variant links:

Genes affected

PPL (HGNC:9273): (periplakin) The protein encoded by this gene is a component of desmosomes and of the epidermal cornified envelope in keratinocytes. The N-terminal domain of this protein interacts with the plasma membrane and its C-terminus interacts with intermediate filaments. Through its rod domain, this protein forms complexes with envoplakin. This protein may serve as a link between the cornified envelope and desmosomes as well as intermediate filaments. AKT1/PKB, a protein kinase mediating a variety of cell growth and survival signaling processes, is reported to interact with this protein, suggesting a possible role for this protein as a localization signal in AKT1-mediated signaling. [provided by RefSeq, Jul 2008]

PPL links:

UBN1 (HGNC:12506): (ubinuclein 1) Cellular senescence is a hallmark of tumor suppression and tissue aging. Senescent cells contain domains of heterochromatin, called senescence-associated heterochromatin foci (SAHF), that repress proliferation-promoting genes. The protein encoded by this gene binds to proliferation-promoting genes and is required for SAHF formation, enhancing methylation of histone H3. [provided by RefSeq, Oct 2016]

UBN1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.65).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.777 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPL	NM_002705.5 link	c.*825A>C		3_prime_UTR_variant	Exon 22 of 22	ENST00000345988.7	NP_002696.4
UBN1	NM_001079514.3 link	c.*2427T>G		downstream_gene_variant		ENST00000262376.11	NP_001072982.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
PPL	ENST00000345988.7 link	c.*825A>C	3_prime_UTR_variant	Exon 22 of 22	1	NM_002705.5	ENSP00000340510.2
UBN1	ENST00000262376.11 link	c.*2427T>G	downstream_gene_variant		1	NM_001079514.3	ENSP00000262376.5
UBN1	ENST00000396658.8 link	c.*2427T>G	downstream_gene_variant		1		ENSP00000379894.3

Frequencies

GnomAD3 genomes

AF:

0.533

AC:

80891

AN:

151712

Hom.:

23603

Cov.:

show subpopulations

Gnomad AFR

AF:

0.784

Gnomad AMI

AF:

0.309

Gnomad AMR

AF:

0.489

Gnomad ASJ

AF:

0.528

Gnomad EAS

AF:

0.355

Gnomad SAS

AF:

0.538

Gnomad FIN

AF:

0.383

Gnomad MID

AF:

0.535

Gnomad NFE

AF:

0.431

Gnomad OTH

AF:

0.517

GnomAD4 exome

AF:

0.161

AC:

AN:

Hom.:

Cov.:

AF XY:

0.158

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.0800

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.400

AC:

AN:

Other (OTH)

AF:

1.00

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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:

0.533

AC:

80998

AN:

151830

Hom.:

23655

Cov.:

AF XY:

0.530

AC XY:

39323

AN XY:

74186

show subpopulations

African (AFR)

AF:

0.784

AC:

32440

AN:

41374

American (AMR)

AF:

0.490

AC:

7471

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.528

AC:

1831

AN:

3466

East Asian (EAS)

AF:

0.355

AC:

1827

AN:

5152

South Asian (SAS)

AF:

0.536

AC:

2581

AN:

4812

European-Finnish (FIN)

AF:

0.383

AC:

4033

AN:

10530

Middle Eastern (MID)

AF:

0.531

AC:

156

AN:

294

European-Non Finnish (NFE)

AF:

0.431

AC:

29283

AN:

67928

Other (OTH)

AF:

0.521

AC:

1095

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

1662

3324

4987

6649

8311

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

684

1368

2052

2736

3420

<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:

0.480

Hom.:

11143

Bravo

AF:

0.556

Asia WGS

AF:

0.518

AC:

1801

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.65

CADD

Benign

7.7

(source)

DANN

Benign

0.69

PhyloP100

0.47

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over