12-42351924-C-G

Variant summary

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

The NM_201439.2(PPHLN1):​c.112C>G​(p.Pro38Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Consequence

PPHLN1
NM_201439.2 missense

Scores

8
11

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.28
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]

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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=0.2935391).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PPHLN1NM_201439.2 linkc.112C>G p.Pro38Ala 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
PPHLN1ENST00000358314.12 linkc.112C>G p.Pro38Ala missense_variant Exon 3 of 10 2 NM_201439.2 ENSP00000351066.7 Q8NEY8-8

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Feb 09, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.112C>G (p.P38A) 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 112, causing the proline (P) at amino acid position 38 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
0.18
BayesDel_addAF
Uncertain
0.046
T
BayesDel_noAF
Benign
-0.17
CADD
Benign
22
DANN
Uncertain
0.99
DEOGEN2
Benign
0.029
T;.;.;T;.;T;.;T;.;T
Eigen
Uncertain
0.30
Eigen_PC
Uncertain
0.34
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Uncertain
0.91
D;D;D;D;D;.;.;D;D;D
M_CAP
Benign
0.0098
T
MetaRNN
Benign
0.29
T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.50
T
MutationAssessor
Uncertain
2.4
.;.;M;M;M;M;M;.;.;.
PrimateAI
Benign
0.46
T
PROVEAN
Uncertain
-2.5
D;D;.;.;D;D;D;D;D;D
REVEL
Benign
0.20
Sift
Benign
0.092
T;T;.;.;T;T;T;T;T;D
Sift4G
Benign
0.40
T;.;T;T;T;T;T;.;T;D
Polyphen
0.99
D;D;.;D;D;D;.;.;.;.
Vest4
0.62
MutPred
0.27
.;.;Loss of glycosylation at P38 (P = 0.0357);Loss of glycosylation at P38 (P = 0.0357);Loss of glycosylation at P38 (P = 0.0357);Loss of glycosylation at P38 (P = 0.0357);Loss of glycosylation at P38 (P = 0.0357);.;Loss of glycosylation at P38 (P = 0.0357);.;
MVP
0.76
MPC
0.31
ClinPred
0.95
D
GERP RS
5.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.072
gMVP
0.27

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-42745726; API