12-42335973-G-A

Variant names:

• chr12-42335973-G-A
• rs548195005
• NM_201439.2:c.71G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_201439.2(PPHLN1):​c.71G>A​(p.Ser24Asn) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000255 in 1,566,636 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S24T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PPHLN1 NM_201439.2 missense, splice_region
• Scores: Splicing: ADA: 0.0002046
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.704
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07913825).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_201439.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPHLN1	NM_201439.2	MANE Select	c.71G>A	p.Ser24Asn	missense splice_region	Exon 2 of 10	NP_958847.1	Q8NEY8-8
	PPHLN1	NM_001364827.2		c.71G>A	p.Ser24Asn	missense splice_region	Exon 2 of 12	NP_001351756.1
	PPHLN1	NM_016488.7		c.71G>A	p.Ser24Asn	missense splice_region	Exon 2 of 13	NP_057572.5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPHLN1	ENST00000358314.12	TSL:2 MANE Select	c.71G>A	p.Ser24Asn	missense splice_region	Exon 2 of 10	ENSP00000351066.7	Q8NEY8-8
	PPHLN1	ENST00000395568.6	TSL:1	c.71G>A	p.Ser24Asn	missense splice_region	Exon 2 of 13	ENSP00000378935.2	Q8NEY8-1
	PPHLN1	ENST00000432191.6	TSL:1	c.71G>A	p.Ser24Asn	missense splice_region	Exon 2 of 12	ENSP00000393965.2	Q8NEY8-3

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151922 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000242

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

GnomAD4 exome AF: 0.00000212 AC: 3 AN: 1414714 Hom.: 0 Cov.: 29 AF XY: 0.00000426 AC XY: 3 AN XY: 703740

African (AFR) AF: 0.0000631 AC: 2 AN: 31706

American (AMR) AF: 0.00 AC: 0 AN: 40918

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25090

East Asian (EAS) AF: 0.00 AC: 0 AN: 37692

South Asian (SAS) AF: 0.00 AC: 0 AN: 78932

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52222

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5620

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1084430

Other (OTH) AF: 0.0000172 AC: 1 AN: 58104

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151922 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74196

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000242 AC: 1 AN: 41384

American (AMR) AF: 0.00 AC: 0 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10502

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68002

Other (OTH) AF: 0.00 AC: 0 AN: 2086

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	15
DANN	Uncertain	0.97
DEOGEN2	Benign	0.0095	T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.079	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.70
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.65	N
REVEL	Benign	0.042
Sift	Benign	0.39	T
Sift4G	Benign	0.52	T
Polyphen		0.016	B
Vest4		0.23
MutPred		0.21		Loss of phosphorylation at S24 (P = 0.0375)
MVP		0.43
MPC		0.20
ClinPred		0.11	T
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.052
gMVP		0.099
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00020
dbscSNV1_RF	Benign	0.048
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

Other links and lift over

dbSNP: rs548195005; hg19: chr12-42729775;