Genetic Variant PAPLN:p.Val443Ile (chr14-73254537-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_001365906.3(PAPLN):c.1327G>A(p.Val443Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00138 in 1,614,020 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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: 𝑓 0.0075 ( 17 hom., cov: 33)

Exomes 𝑓: 0.00075 ( 20 hom. )

Consequence

PAPLN
NM_001365906.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.671

Publications

10 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005782604).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00745 (1135/152316) while in subpopulation AFR AF = 0.0264 (1098/41570). AF 95% confidence interval is 0.0251. There are 17 homozygotes in GnomAd4. There are 524 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 17 AR gene

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
PAPLN	NM_001365906.3	MANE Select	c.1327G>A	p.Val443Ile	missense	Exon 13 of 27	NP_001352835.1
PAPLN	NM_001365907.2		c.1327G>A	p.Val443Ile	missense	Exon 12 of 26	NP_001352836.1
PAPLN	NM_173462.4		c.1246G>A	p.Val416Ile	missense	Exon 12 of 26	NP_775733.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PAPLN	ENST00000644200.2	MANE Select	c.1327G>A	p.Val443Ile	missense	Exon 13 of 27	ENSP00000495882.2
PAPLN	ENST00000216658.9	TSL:1	n.1327G>A		non_coding_transcript_exon	Exon 13 of 27	ENSP00000216658.5
PAPLN	ENST00000555123.5	TSL:1	n.1246G>A		non_coding_transcript_exon	Exon 12 of 24	ENSP00000452455.1

Frequencies

GnomAD3 genomes

AF:

0.00746

AC:

1135

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00150

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00431

GnomAD2 exomes

AF:

0.00186

AC:

467

AN:

251156

AF XY:

0.00139

show subpopulations

Gnomad AFR exome

AF:

0.0258

Gnomad AMR exome

AF:

0.000752

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000115

Gnomad OTH exome

AF:

0.000816

GnomAD4 exome

AF:

0.000746

AC:

1091

AN:

1461704

Hom.:

Cov.:

AF XY:

0.000661

AC XY:

481

AN XY:

727178

show subpopulations

African (AFR)

AF:

0.0271

AC:

906

AN:

33476

American (AMR)

AF:

0.000917

AC:

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26110

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.000694

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000324

AC:

AN:

1111896

Other (OTH)

AF:

0.00154

AC:

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

126

190

253

316

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

150

<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

AF:

0.00745

AC:

1135

AN:

152316

Hom.:

Cov.:

AF XY:

0.00703

AC XY:

524

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.0264

AC:

1098

AN:

41570

American (AMR)

AF:

0.00150

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000414

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68014

Other (OTH)

AF:

0.00427

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

110

164

219

274

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00391

Hom.:

Bravo

AF:

0.00832

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0245

AC:

108

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00238

AC:

289

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000119

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.69

CADD

Benign

0.51

(source)

DANN

Benign

0.54

DEOGEN2

Benign

0.0044

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.089

LIST_S2

Benign

0.083

MetaRNN

Benign

0.0058

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.43

PhyloP100

0.67

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.50

REVEL

Benign

0.010

Sift

Benign

0.51

Sift4G

Benign

0.44

Polyphen

0.0060

Vest4

0.063

MVP

0.076

MPC

0.15

ClinPred

0.0016

GERP RS

-2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.023

gMVP

0.099

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over