12-42393656-T-G

Variant summary

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

The NM_201439.2(PPHLN1):c.735T>G(p.Asp245Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,457,364 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D245G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: PPHLN1 NM_201439.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.749

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=0.10646704).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPHLN1	NM_201439.2	c.735T>G	p.Asp245Glu	missense_variant	8/10	ENST00000358314.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPHLN1	ENST00000358314.12	c.735T>G	p.Asp245Glu	missense_variant	8/10	2	NM_201439.2	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1457364 Hom.: 0 Cov.: 30 AF XY: 0.00000414 AC XY: 3 AN XY: 725108

Gnomad4 AFR exome AF: 0.0000601

Gnomad4 AMR exome AF: 0.0000230

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: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000189

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

Dec 28, 2023

The c.735T>G (p.D245E) alteration is located in exon 8 (coding exon 7) of the PPHLN1 gene. This alteration results from a T to G substitution at nucleotide position 735, causing the aspartic acid (D) at amino acid position 245 to be replaced by a glutamic acid (E). 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	0.16
BayesDel_addAF	Benign	-0.064	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	15
Dann	Uncertain	0.99
DEOGEN2	Benign	0.023	T;.;T;.;.;T;.;T;.;.;.;.;.
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.082
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.81	T;T;T;T;T;T;T;.;T;.;T;T;.
M_CAP	Benign	0.0021	T
MetaRNN	Benign	0.11	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.89	N;N;N;N;N;N;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.2	N;N;N;.;.;.;N;N;N;N;N;N;N
REVEL	Benign	0.082
Sift	Benign	0.31	T;T;T;.;.;.;T;T;T;T;T;T;T
Sift4G	Benign	0.66	T;.;T;T;T;T;T;T;T;T;.;.;T
Polyphen		0.0090	B;B;B;.;B;B;B;B;B;.;B;B;B
Vest4		0.10
MutPred		0.087		.;.;.;.;.;Gain of methylation at K240 (P = 0.1278);Gain of methylation at K240 (P = 0.1278);Gain of methylation at K240 (P = 0.1278);.;.;.;.;.;
MVP		0.56
MPC		0.28
ClinPred		0.34	T
GERP RS		3.7
Varity_R		0.044
gMVP		0.068

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

LitVar

Other links and lift over

dbSNP: rs1565922536; hg19: chr12-42787458;