Variant 12-42352035-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_201439.2(PPHLN1):c.223C>G(p.Pro75Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000727 in 1,375,604 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 31)

Exomes 𝑓: 7.3e-7 ( 0 hom. )

Consequence

PPHLN1
NM_201439.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

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:

PPHLN1 (HGNC:):

PPHLN1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.26501217).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPHLN1	NM_201439.2 linkuse as main transcript	c.223C>G	p.Pro75Ala	missense_variant	3/10	ENST00000358314.12	NP_958847.1	Q8NEY8-8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPHLN1	ENST00000358314.12 linkuse as main transcript	c.223C>G	p.Pro75Ala	missense_variant	3/10	2	NM_201439.2	ENSP00000351066.7		Q8NEY8-8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000540

AC:

AN:

185346

Hom.:

AF XY:

0.00000982

AC XY:

AN XY:

101814

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000109

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.27e-7

AC:

AN:

1375604

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

681584

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

9.30e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

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

Nov 15, 2024

The c.223C>G (p.P75A) alteration is located in exon 3 (coding exon 2) of the PPHLN1 gene. This alteration results from a C to G substitution at nucleotide position 223, causing the proline (P) at amino acid position 75 to be replaced by an alanine (A). 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

0.25

BayesDel_addAF

Benign

-0.026

BayesDel_noAF

Benign

-0.28

CADD

Uncertain

DANN

Benign

0.97

DEOGEN2

Benign

0.13

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

Eigen

Uncertain

0.22

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.92

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

M_CAP

Benign

0.0019

MetaRNN

Benign

0.27

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

MetaSVM

Benign

-0.81

MutationAssessor

Uncertain

2.3

.;.;M;M;M;M;M;.;.

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-3.0

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

REVEL

Benign

0.10

Sift

Benign

0.042

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

Sift4G

Benign

0.069

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

Polyphen

0.40

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

Vest4

0.50

MutPred

0.20

.;.;Gain of MoRF binding (P = 0.0481);Gain of MoRF binding (P = 0.0481);Gain of MoRF binding (P = 0.0481);Gain of MoRF binding (P = 0.0481);Gain of MoRF binding (P = 0.0481);.;Gain of MoRF binding (P = 0.0481);

MVP

0.74

MPC

0.27

ClinPred

0.59

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.10

gMVP

0.27

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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