16-4883839-T-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.659

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]

ACMG classification

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	UniProt
PPL	NM_002705.5	c.4816A>T	p.Thr1606Ser	missense_variant	22/22	ENST00000345988.7
PPL	XM_017023374.3	c.4903A>T	p.Thr1635Ser	missense_variant	22/22
PPL	XM_017023375.3	c.4864A>T	p.Thr1622Ser	missense_variant	22/22
PPL	XM_006720902.5	c.4855A>T	p.Thr1619Ser	missense_variant	22/22

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152194 Hom.: 0 Cov.: 32

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: 21 AN: 251392 Hom.: 0 AF XY: 0.0000589 AC XY: 8 AN XY: 135874

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: 68 AN: 1461804 Hom.: 0 Cov.: 34 AF XY: 0.0000440 AC XY: 32 AN XY: 727204

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: 6 AN: 152194 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74352

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.: 0

Bravo AF: 0.0000869

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

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	T
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	N
LIST_S2	Benign	0.49	T;T;T
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.015	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.21	T
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	T
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

Other links and lift over

dbSNP: rs146564793; hg19: chr16-4933840;