Variant 12-42335973-G-C details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_201439.2(PPHLN1):c.71G>C(p.Ser24Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000255 in 1,566,754 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

PPHLN1
NM_201439.2 missense, splice_region

Scores

Splicing: ADA: 0.00004517

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.704

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 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=0.061579525).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPHLN1	NM_201439.2 linkuse as main transcript	c.71G>C	p.Ser24Thr	missense_variant, splice_region_variant	2/10	ENST00000358314.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPHLN1	ENST00000358314.12 linkuse as main transcript	c.71G>C	p.Ser24Thr	missense_variant, splice_region_variant	2/10	2	NM_201439.2	A1	Q8NEY8-8

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151922

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

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

GnomAD3 exomes

AF:

0.0000173

AC:

AN:

231040

Hom.:

AF XY:

0.00000796

AC XY:

AN XY:

125606

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000249

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000212

AC:

AN:

1414714

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

703740

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000796

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152040

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000247

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

Oct 14, 2023

The c.71G>C (p.S24T) alteration is located in exon 2 (coding exon 1) of the PPHLN1 gene. This alteration results from a G to C substitution at nucleotide position 71, causing the serine (S) at amino acid position 24 to be replaced by a threonine (T). 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

0.082

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.026

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

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.26

LIST_S2

Uncertain

0.91

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

M_CAP

Benign

0.0045

MetaRNN

Benign

0.062

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

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

MutationTaster

Benign

1.0

D;N;N;N;N;N;N

PrimateAI

Benign

0.38

PROVEAN

Benign

-1.3

N;N;N;.;.;.;N;N;N;N;N;N;N;N

REVEL

Benign

0.025

Sift

Benign

0.24

T;T;T;.;.;.;T;T;T;D;T;D;T;D

Sift4G

Benign

0.28

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

Polyphen

0.33

B;B;B;.;B;P;B;P;.;B;B;B;.;.

Vest4

0.29

MutPred

0.28

.;.;Gain of catalytic residue at S24 (P = 0.0291);Gain of catalytic residue at S24 (P = 0.0291);Gain of catalytic residue at S24 (P = 0.0291);Gain of catalytic residue at S24 (P = 0.0291);Gain of catalytic residue at S24 (P = 0.0291);Gain of catalytic residue at S24 (P = 0.0291);Gain of catalytic residue at S24 (P = 0.0291);.;.;Gain of catalytic residue at S24 (P = 0.0291);.;Gain of catalytic residue at S24 (P = 0.0291);

MVP

0.54

MPC

0.19

ClinPred

0.076

GERP RS

1.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.083

gMVP

0.12

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000045

dbscSNV1_RF

Benign

0.0040

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