Genetic Variant PAPLN:p.Pro143Arg (chr14-73250077-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_001365906.3(PAPLN):c.428C>G(p.Pro143Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,132 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P143L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PAPLN
NM_001365906.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.01

Publications

0 publications found

Variant links:

Genes affected

PAPLN (HGNC:19262): (papilin, proteoglycan like sulfated glycoprotein) Predicted to enable metalloendopeptidase activity. Predicted to be involved in extracellular matrix organization. Predicted to be located in basement membrane. Predicted to be active in extracellular matrix. [provided by Alliance of Genome Resources, Apr 2022]

PAPLN links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001365906.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PAPLN	NM_001365906.3	MANE Select	c.428C>G	p.Pro143Arg	missense	Exon 6 of 27	NP_001352835.1	O95428-1
PAPLN	NM_001365907.2		c.428C>G	p.Pro143Arg	missense	Exon 5 of 26	NP_001352836.1	O95428-5
PAPLN	NM_173462.4		c.428C>G	p.Pro143Arg	missense	Exon 6 of 26	NP_775733.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PAPLN	ENST00000644200.2	MANE Select	c.428C>G	p.Pro143Arg	missense	Exon 6 of 27	ENSP00000495882.2	O95428-1
PAPLN	ENST00000216658.9	TSL:1	n.428C>G		non_coding_transcript_exon	Exon 6 of 27	ENSP00000216658.5	B5MDP7
PAPLN	ENST00000555123.5	TSL:1	n.428C>G		non_coding_transcript_exon	Exon 6 of 24	ENSP00000452455.1	G3V5P6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460132

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726224

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

33414

American (AMR)

AF:

0.00

AC:

AN:

44460

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26084

East Asian (EAS)

AF:

0.00

AC:

AN:

39620

South Asian (SAS)

AF:

0.00

AC:

AN:

85862

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53284

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111320

Other (OTH)

AF:

0.00

AC:

AN:

60334

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Uncertain

0.076

BayesDel_noAF

Benign

-0.13

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.059

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.85

M_CAP

Benign

0.021

MetaRNN

Uncertain

0.68

MetaSVM

Uncertain

-0.20

MutationAssessor

Uncertain

2.5

PhyloP100

5.0

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-6.6

REVEL

Uncertain

0.35

Sift

Uncertain

0.018

Sift4G

Uncertain

0.015

Polyphen

1.0

Vest4

0.71

MutPred

0.36

Loss of catalytic residue at P143 (P = 0.0736)

MVP

0.61

MPC

0.76

ClinPred

0.98

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.51

gMVP

0.73

Mutation Taster

=79/21

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over