Variant 14-73251028-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001365906.3(PAPLN):c.587G>A(p.Arg196Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000559 in 1,610,536 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000053 ( 0 hom. )

Consequence

PAPLN
NM_001365906.3 missense, splice_region

Scores

Splicing: ADA: 0.05167

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.38

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 made for transcript

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=0.16422978).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAPLN	NM_001365906.3 linkuse as main transcript	c.587G>A	p.Arg196Gln	missense_variant, splice_region_variant	7/27	ENST00000644200.2	NP_001352835.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAPLN	ENST00000644200.2 linkuse as main transcript	c.587G>A	p.Arg196Gln	missense_variant, splice_region_variant	7/27		NM_001365906.3	ENSP00000495882	P1	O95428-1

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000768

AC:

AN:

247422

Hom.:

AF XY:

0.0000822

AC XY:

AN XY:

133800

show subpopulations

Gnomad AFR exome

AF:

0.000309

Gnomad AMR exome

AF:

0.0000292

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000332

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000107

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000528

AC:

AN:

1458186

Hom.:

Cov.:

AF XY:

0.0000565

AC XY:

AN XY:

725298

show subpopulations

Gnomad4 AFR exome

AF:

0.000150

Gnomad4 AMR exome

AF:

0.0000225

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000349

Gnomad4 FIN exome

AF:

0.0000191

Gnomad4 NFE exome

AF:

0.0000513

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.0000853

AC:

AN:

152350

Hom.:

Cov.:

AF XY:

0.0000671

AC XY:

AN XY:

74506

show subpopulations

Gnomad4 AFR

AF:

0.000192

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000724

Hom.:

Bravo

AF:

0.000113

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000741

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 05, 2023

The c.587G>A (p.R196Q) alteration is located in exon 7 (coding exon 6) of the PAPLN gene. This alteration results from a G to A substitution at nucleotide position 587, causing the arginine (R) at amino acid position 196 to be replaced by a glutamine (Q). 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

Benign

0.12

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.14

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0078

T;.;T;.

Eigen

Benign

-0.086

Eigen_PC

Benign

-0.0028

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.91

D;T;.;D

M_CAP

Benign

0.034

MetaRNN

Benign

0.14

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.2

M;M;M;M

MutationTaster

Benign

1.0

N;N;N;N;N

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.9

.;N;N;N

REVEL

Benign

0.22

Sift

Benign

0.25

.;T;T;T

Sift4G

Uncertain

0.058

.;T;D;T

Polyphen

0.30

B;P;B;B

Vest4

0.46, 0.43, 0.40

MVP

0.60

MPC

0.55

ClinPred

0.055

GERP RS

2.5

Varity_R

0.095

gMVP

0.41

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.052

dbscSNV1_RF

Benign

0.38

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over