dbSNP rs776469029: PPHLN1:p.Pro75Thr (chr12-42352035-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_201439.2(PPHLN1):c.223C>A(p.Pro75Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000017 in 1,527,592 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

PPHLN1
NM_201439.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.37

Variant links:

Genes affected

PPHLN1 (HGNC:19369): (periphilin 1) The protein encoded by this gene is one of the several proteins that become sequentially incorporated into the cornified cell envelope during the terminal differentiation of keratinocyte at the outer layers of epidermis. This protein interacts with periplakin, which is known as a precursor of the cornified cell envelope. The cellular localization pattern and insolubility of this protein suggest that it may play a role in epithelial differentiation and contribute to epidermal integrity and barrier formation. Multiple alternatively spliced transcript variants encoding distinct isoforms have been observed. [provided by RefSeq, Jul 2008]

PPHLN1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.23720098).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPHLN1	NM_201439.2 link	c.223C>A	p.Pro75Thr	missense_variant	Exon 3 of 10	ENST00000358314.12	NP_958847.1	Q8NEY8-8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPHLN1	ENST00000358314.12 link	c.223C>A	p.Pro75Thr	missense_variant	Exon 3 of 10	2	NM_201439.2	ENSP00000351066.7		Q8NEY8-8

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151988

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

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:

0.00

GnomAD4 exome

AF:

0.0000174

AC:

AN:

1375604

Hom.:

Cov.:

AF XY:

0.0000103

AC XY:

AN XY:

681584

show subpopulations

Gnomad4 AFR exome

AF:

0.0000350

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000214

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151988

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74224

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

-0.077

BayesDel_noAF

Benign

-0.35

CADD

Uncertain

DANN

Benign

0.94

DEOGEN2

Benign

0.057

T;.;.;T;.;T;.;T;.

Eigen

Benign

0.029

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.84

T;T;T;T;T;.;.;T;T

M_CAP

Benign

0.0013

MetaRNN

Benign

0.24

T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.6

.;.;L;L;L;L;L;.;.

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-3.2

D;D;.;.;D;D;D;D;D

REVEL

Benign

0.060

Sift

Benign

0.12

T;T;.;.;T;T;T;T;T

Sift4G

Benign

0.22

T;.;T;T;T;T;T;.;T

Polyphen

0.010

B;B;.;B;B;B;.;.;.

Vest4

0.36

MutPred

0.30

.;.;Gain of phosphorylation at P75 (P = 9e-04);Gain of phosphorylation at P75 (P = 9e-04);Gain of phosphorylation at P75 (P = 9e-04);Gain of phosphorylation at P75 (P = 9e-04);Gain of phosphorylation at P75 (P = 9e-04);.;Gain of phosphorylation at P75 (P = 9e-04);

MVP

0.66

MPC

0.33

ClinPred

0.62

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.18

gMVP

0.34

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over