12-42374895-T-C

Position:

• chr12-42374895-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_201439.2(PPHLN1):​c.332T>C​(p.Phe111Ser) 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: 30)
• Consequence: PPHLN1 NM_201439.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.44

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]

ACMG classification

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=0.19506088).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPHLN1	NM_201439.2	c.332T>C	p.Phe111Ser	missense_variant	5/10	ENST00000358314.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPHLN1	ENST00000358314.12	c.332T>C	p.Phe111Ser	missense_variant	5/10	2	NM_201439.2	A1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 04, 2024

The c.332T>C (p.F111S) alteration is located in exon 5 (coding exon 4) of the PPHLN1 gene. This alteration results from a T to C substitution at nucleotide position 332, causing the phenylalanine (F) at amino acid position 111 to be replaced by a serine (S). 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	Uncertain	0.49
BayesDel_addAF	Benign	0.0046	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.025	T;.;T;.;.;T;.;T;.;.;.;.;.;T;.
Eigen	Benign	0.13
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.78	T;T;T;T;T;T;T;.;T;.;T;T;.;T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.20	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.6	.;.;.;L;.;L;L;L;.;L;.;.;.;.;.
MutationTaster	Benign	0.90	D;D;N;N;N;N;N
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.9	N;N;N;.;.;.;N;N;N;N;N;N;N;D;D
REVEL	Benign	0.096
Sift	Benign	0.24	T;T;T;.;.;.;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.41	T;.;T;T;T;T;T;T;T;T;.;.;T;.;T
Polyphen		0.84	P;P;P;.;D;D;P;D;D;.;P;B;D;.;.
Vest4		0.31
MutPred		0.26		.;.;.;Gain of phosphorylation at F111 (P = 0.0031);.;Gain of phosphorylation at F111 (P = 0.0031);Gain of phosphorylation at F111 (P = 0.0031);Gain of phosphorylation at F111 (P = 0.0031);.;Gain of phosphorylation at F111 (P = 0.0031);.;.;.;.;Gain of phosphorylation at F111 (P = 0.0031);
MVP		0.66
MPC		0.72
ClinPred		0.71	D
GERP RS		3.7
Varity_R		0.13
gMVP		0.18

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: chr12-42768697;