12-42374958-A-G

Variant names:

• chr12-42374958-A-G
• rs2076131047
• NM_201439.2:c.395A>G

Variant summary

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

The NM_201439.2(PPHLN1):​c.395A>G​(p.Glu132Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: PPHLN1 NM_201439.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.47

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPHLN1	NM_201439.2	c.395A>G	p.Glu132Gly	missense_variant	Exon 5 of 10	ENST00000358314.12	NP_958847.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPHLN1	ENST00000358314.12	c.395A>G	p.Glu132Gly	missense_variant	Exon 5 of 10	2	NM_201439.2	ENSP00000351066.7

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.395A>G (p.E132G) alteration is located in exon 5 (coding exon 4) of the PPHLN1 gene. This alteration results from a A to G substitution at nucleotide position 395, causing the glutamic acid (E) at amino acid position 132 to be replaced by a glycine (G). 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	0.51
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.079	T;.;T;.;.;D;.;D;.;.;.;.;.;T;.
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.86	D;D;D;T;T;D;D;.;T;.;D;T;.;T;T
M_CAP	Benign	0.014	T
MetaRNN	Uncertain	0.54	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Uncertain	2.3	.;.;.;M;.;M;M;M;.;M;.;.;.;.;.
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-3.8	D;D;D;.;.;.;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.51
Sift	Uncertain	0.0010	D;D;D;.;.;.;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.031	D;.;D;D;D;D;D;D;T;D;.;.;D;.;D
Polyphen		1.0	D;D;D;.;D;D;D;D;D;.;D;D;D;.;.
Vest4		0.20
MutPred		0.28		.;.;.;Gain of MoRF binding (P = 0.0267);.;Gain of MoRF binding (P = 0.0267);Gain of MoRF binding (P = 0.0267);Gain of MoRF binding (P = 0.0267);.;Gain of MoRF binding (P = 0.0267);.;.;.;.;Gain of MoRF binding (P = 0.0267);
MVP		0.79
MPC		0.26
ClinPred		0.99	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.30
gMVP		0.24

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: rs2076131047; hg19: chr12-42768760;