dbSNP rs548195005: PPHLN1:p.Ser24Asn (chr12-42335973-G-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.71G>A(p.Ser24Asn) 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 1,566,636 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

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: 0.0002046

Clinical Significance

Not reported in ClinVar

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 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=0.07913825).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPHLN1	NM_201439.2 link	c.71G>A	p.Ser24Asn	missense_variant, splice_region_variant	Exon 2 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.71G>A	p.Ser24Asn	missense_variant, splice_region_variant	Exon 2 of 10	2	NM_201439.2	ENSP00000351066.7		Q8NEY8-8

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151922

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.00000212

AC:

AN:

1414714

Hom.:

Cov.:

AF XY:

0.00000426

AC XY:

AN XY:

703740

show subpopulations

Gnomad4 AFR exome

AF:

0.0000631

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:

0.00

Gnomad4 OTH exome

AF:

0.0000172

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151922

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74196

show subpopulations

Gnomad4 AFR

AF:

0.0000242

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

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Uncertain

0.97

DEOGEN2

Benign

0.0095

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

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.49

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.79

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

M_CAP

Benign

0.0040

MetaRNN

Benign

0.079

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

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

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

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.65

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

REVEL

Benign

0.042

Sift

Benign

0.39

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

Sift4G

Benign

0.52

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

Polyphen

0.016

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

Vest4

0.23

MutPred

0.21

.;.;Loss of phosphorylation at S24 (P = 0.0375);Loss of phosphorylation at S24 (P = 0.0375);Loss of phosphorylation at S24 (P = 0.0375);Loss of phosphorylation at S24 (P = 0.0375);Loss of phosphorylation at S24 (P = 0.0375);Loss of phosphorylation at S24 (P = 0.0375);Loss of phosphorylation at S24 (P = 0.0375);.;.;Loss of phosphorylation at S24 (P = 0.0375);.;Loss of phosphorylation at S24 (P = 0.0375);

MVP

0.43

MPC

0.20

ClinPred

0.11

GERP RS

1.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.052

gMVP

0.099

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00020

dbscSNV1_RF

Benign

0.048

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over