16-4883616-A-G

Variant names:

• chr16-4883616-A-G
• rs1395990605
• NM_002705.5:c.5039T>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_002705.5(PPL):​c.5039T>C​(p.Ile1680Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: PPL NM_002705.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32

Genes affected

PPL (HGNC:9273): (periplakin) The protein encoded by this gene is a component of desmosomes and of the epidermal cornified envelope in keratinocytes. The N-terminal domain of this protein interacts with the plasma membrane and its C-terminus interacts with intermediate filaments. Through its rod domain, this protein forms complexes with envoplakin. This protein may serve as a link between the cornified envelope and desmosomes as well as intermediate filaments. AKT1/PKB, a protein kinase mediating a variety of cell growth and survival signaling processes, is reported to interact with this protein, suggesting a possible role for this protein as a localization signal in AKT1-mediated signaling. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.878

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPL	NM_002705.5	c.5039T>C	p.Ile1680Thr	missense_variant	Exon 22 of 22	ENST00000345988.7	NP_002696.4
PPL	XM_017023374.3	c.5126T>C	p.Ile1709Thr	missense_variant	Exon 22 of 22		XP_016878863.1
PPL	XM_017023375.3	c.5087T>C	p.Ile1696Thr	missense_variant	Exon 22 of 22		XP_016878864.1
PPL	XM_006720902.5	c.5078T>C	p.Ile1693Thr	missense_variant	Exon 22 of 22		XP_006720965.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPL	ENST00000345988.7	c.5039T>C	p.Ile1680Thr	missense_variant	Exon 22 of 22	1	NM_002705.5	ENSP00000340510.2
PPL	ENST00000590782.6	c.5033T>C	p.Ile1678Thr	missense_variant	Exon 22 of 22	5		ENSP00000465640.1
PPL	ENST00000592772.1	c.3302T>C	p.Ile1101Thr	missense_variant	Exon 10 of 10	5		ENSP00000467699.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461864 Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2 AN XY: 727232

Gnomad4 AFR exome AF: 0.00

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: 0.00000809

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 25, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5039T>C (p.I1680T) alteration is located in exon 22 (coding exon 22) of the PPL gene. This alteration results from a T to C substitution at nucleotide position 5039, causing the isoleucine (I) at amino acid position 1680 to be replaced by a threonine (T). 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	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D;.;T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.88	D;D;D
MetaSVM	Uncertain	0.45	D
MutationAssessor	Pathogenic	3.0	M;.;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-4.2	D;.;.
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0010	D;.;.
Sift4G	Uncertain	0.0020	D;D;.
Polyphen		1.0	D;.;.
Vest4		0.89
MutPred		0.68		Loss of stability (P = 0.0363);.;.;
MVP		0.94
MPC		0.17
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.82
gMVP		0.67

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: rs1395990605; hg19: chr16-4933617;