12-42355163-T-A

Variant names:

• chr12-42355163-T-A
• rs138475402
• NM_201439.2:c.240T>A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_201439.2(PPHLN1):​c.240T>A​(p.Asp80Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000651 in 1,613,490 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00037 (2 hom., cov: 32)
  • Exomes 𝑓: 0.000033 (0 hom.)
• Consequence: PPHLN1 NM_201439.2 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.09

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 Likely_benign. Variant got -4 ACMG points.

• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPHLN1	NM_201439.2	c.240T>A	p.Asp80Glu	missense_variant, splice_region_variant	Exon 4 of 10	ENST00000358314.12	NP_958847.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPHLN1	ENST00000358314.12	c.240T>A	p.Asp80Glu	missense_variant, splice_region_variant	Exon 4 of 10	2	NM_201439.2	ENSP00000351066.7

Frequencies

GnomAD3 genomes AF: 0.000309 AC: 47 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00113

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

GnomAD3 exomes AF: 0.0000716 AC: 18 AN: 251364 Hom.: 0 AF XY: 0.0000515 AC XY: 7 AN XY: 135856

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000328 AC: 48 AN: 1461202 Hom.: 0 Cov.: 30 AF XY: 0.0000289 AC XY: 21 AN XY: 726908

Gnomad4 AFR exome AF: 0.00120

Gnomad4 AMR exome AF: 0.0000447

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: 0.0000994

GnomAD4 genome AF: 0.000374 AC: 57 AN: 152288 Hom.: 2 Cov.: 32 AF XY: 0.000483 AC XY: 36 AN XY: 74468

Gnomad4 AFR AF: 0.00137

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

Alfa AF: 0.0000911 Hom.: 0

Bravo AF: 0.000423

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000115 AC: 14

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 16, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.240T>A (p.D80E) alteration is located in exon 4 (coding exon 3) of the PPHLN1 gene. This alteration results from a T to A substitution at nucleotide position 240, causing the aspartic acid (D) at amino acid position 80 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	0.32
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.030	T;.;T;.;.;T;.;T;.;.;.;.;T;.
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.81	T;T;T;T;T;T;T;.;.;T;T;.;T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.054	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Uncertain	2.1	.;.;.;M;.;M;M;M;M;.;.;.;.;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.1	N;N;N;.;.;.;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.32
Sift	Uncertain	0.0030	D;D;D;.;.;.;D;D;D;D;D;D;D;D
Sift4G	Benign	0.50	T;.;T;T;T;T;T;T;T;.;.;T;.;T
Polyphen		0.91	P;P;D;.;D;P;P;P;.;P;P;D;.;.
Vest4		0.30
MutPred		0.23		.;.;.;Gain of solvent accessibility (P = 0.0306);.;Gain of solvent accessibility (P = 0.0306);Gain of solvent accessibility (P = 0.0306);Gain of solvent accessibility (P = 0.0306);Gain of solvent accessibility (P = 0.0306);.;.;.;.;Gain of solvent accessibility (P = 0.0306);
MVP		0.68
MPC		0.73
ClinPred		0.12	T
GERP RS		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.094

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.31		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.31		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs138475402; hg19: chr12-42748965;