chr12-42374867-A-T

Variant names:

• chr12-42374867-A-T
• NM_201439.2:c.304A>T

Variant summary

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

The NM_201439.2(PPHLN1):​c.304A>T​(p.Met102Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000276 in 1,450,038 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: PPHLN1 NM_201439.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.06

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=0.1466037).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPHLN1	NM_201439.2	c.304A>T	p.Met102Leu	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.304A>T	p.Met102Leu	missense_variant	Exon 5 of 10	2	NM_201439.2	ENSP00000351066.7

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000276 AC: 4 AN: 1450038 Hom.: 0 Cov.: 32 AF XY: 0.00000416 AC XY: 3 AN XY: 721804

Gnomad4 AFR exome AF: 0.0000306

Gnomad4 AMR exome AF: 0.00

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: 0.00000271

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.069	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	13
DANN	Benign	0.91
DEOGEN2	Benign	0.023	T;.;T;.;.;T;.;T;.;.;.;.;.;T;.
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D;D;.;D;.;D;D;.;D;D
M_CAP	Benign	0.0069	T
MetaRNN	Benign	0.053	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	2.0	.;.;.;M;.;M;M;M;.;M;.;.;.;.;.
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.1	N;N;N;.;.;.;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.034
Sift	Benign	0.34	T;T;T;.;.;.;T;T;D;T;T;T;T;T;T
Sift4G	Benign	0.30	T;.;T;T;T;T;T;T;T;T;.;.;T;.;T
Polyphen		0.027	B;B;B;.;B;B;B;B;P;.;B;B;B;.;.
Vest4		0.26
MutPred		0.28		.;.;.;Loss of MoRF binding (P = 0.0817);.;Loss of MoRF binding (P = 0.0817);Loss of MoRF binding (P = 0.0817);Loss of MoRF binding (P = 0.0817);.;Loss of MoRF binding (P = 0.0817);.;.;.;.;Loss of MoRF binding (P = 0.0817);
MVP		0.36
MPC		0.23
ClinPred		0.17	T
GERP RS		-0.40
Varity_R		0.060
gMVP		0.093

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr12-42768669;