16-4883839-T-A

Position:

chr16-4883839-T-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_002705.5(PPL):c.4816A>T(p.Thr1606Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000458 in 1,613,998 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000047 ( 0 hom. )

Consequence

PPL
NM_002705.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.659

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.015115857).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
PPL	NM_002705.5 linkuse as main transcript	c.4816A>T	p.Thr1606Ser	missense_variant	22/22	ENST00000345988.7	NP_002696.4
PPL	XM_017023374.3 linkuse as main transcript	c.4903A>T	p.Thr1635Ser	missense_variant	22/22		XP_016878863.1
PPL	XM_017023375.3 linkuse as main transcript	c.4864A>T	p.Thr1622Ser	missense_variant	22/22		XP_016878864.1
PPL	XM_006720902.5 linkuse as main transcript	c.4855A>T	p.Thr1619Ser	missense_variant	22/22		XP_006720965.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
PPL	ENST00000345988.7 linkuse as main transcript	c.4816A>T	p.Thr1606Ser	missense_variant	22/22	1	NM_002705.5	ENSP00000340510	P3
PPL	ENST00000590782.6 linkuse as main transcript	c.4810A>T	p.Thr1604Ser	missense_variant	22/22	5		ENSP00000465640	A1
PPL	ENST00000592772.1 linkuse as main transcript	c.3079A>T	p.Thr1027Ser	missense_variant	10/10	5		ENSP00000467699

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000835

AC:

AN:

251392

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135874

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00139

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000465

AC:

AN:

1461804

Hom.:

Cov.:

AF XY:

0.0000440

AC XY:

AN XY:

727204

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.00191

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000629

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000137

Hom.:

Bravo

AF:

0.0000869

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 20, 2022

The c.4816A>T (p.T1606S) alteration is located in exon 22 (coding exon 22) of the PPL gene. This alteration results from a A to T substitution at nucleotide position 4816, causing the threonine (T) at amino acid position 1606 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.56

CADD

Benign

0.69

DANN

Benign

0.66

DEOGEN2

Benign

0.089

T;.;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.43

LIST_S2

Benign

0.49

T;T;T

M_CAP

Benign

0.0076

MetaRNN

Benign

0.015

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.0

L;.;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.21

PROVEAN

Benign

-0.21

N;.;.

REVEL

Benign

0.059

Sift

Benign

0.74

T;.;.

Sift4G

Benign

0.73

T;T;.

Polyphen

0.078

B;.;.

Vest4

0.090

MutPred

0.12

Loss of catalytic residue at T1606 (P = 0.0615);.;.;

MVP

0.54

MPC

0.019

ClinPred

0.014

GERP RS

-5.0

Varity_R

0.033

gMVP

0.14

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