chr14-73251759-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001365906.3(PAPLN):​c.766G>A​(p.Glu256Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000992 in 1,612,464 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: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

PAPLN
NM_001365906.3 missense

Scores

2
7
10

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.11
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.763

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PAPLNNM_001365906.3 linkuse as main transcriptc.766G>A p.Glu256Lys missense_variant 9/27 ENST00000644200.2 NP_001352835.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PAPLNENST00000644200.2 linkuse as main transcriptc.766G>A p.Glu256Lys missense_variant 9/27 NM_001365906.3 ENSP00000495882 P1O95428-1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152180
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000403
AC:
1
AN:
248290
Hom.:
0
AF XY:
0.00000742
AC XY:
1
AN XY:
134854
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000894
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000959
AC:
14
AN:
1460284
Hom.:
0
Cov.:
33
AF XY:
0.00000826
AC XY:
6
AN XY:
726434
show subpopulations
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:
0.0000108
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152180
Hom.:
0
Cov.:
33
AF XY:
0.0000135
AC XY:
1
AN XY:
74338
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000329
Hom.:
0

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 submitterclinical testingAmbry GeneticsJun 22, 2024The c.685G>A (p.E229K) alteration is located in exon 8 (coding exon 7) of the PAPLN gene. This alteration results from a G to A substitution at nucleotide position 685, causing the glutamic acid (E) at amino acid position 229 to be replaced by a lysine (K). 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
0.15
BayesDel_addAF
Benign
-0.045
T
BayesDel_noAF
Benign
-0.30
CADD
Uncertain
24
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.018
T;.;T;.
Eigen
Uncertain
0.44
Eigen_PC
Uncertain
0.44
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Uncertain
0.91
D;D;.;D
M_CAP
Benign
0.034
D
MetaRNN
Pathogenic
0.76
D;D;D;D
MetaSVM
Benign
-0.81
T
MutationAssessor
Benign
1.5
L;.;L;L
MutationTaster
Benign
0.96
D;D;D;D;D
PrimateAI
Uncertain
0.53
T
PROVEAN
Uncertain
-2.8
.;D;D;D
REVEL
Benign
0.24
Sift
Uncertain
0.015
.;D;D;D
Sift4G
Benign
0.071
.;T;T;T
Polyphen
1.0
D;D;D;D
Vest4
0.69, 0.67, 0.69
MutPred
0.69
Gain of methylation at E256 (P = 0.0062);.;Gain of methylation at E256 (P = 0.0062);Gain of methylation at E256 (P = 0.0062);
MVP
0.41
MPC
0.62
ClinPred
0.91
D
GERP RS
4.8
Varity_R
0.18
gMVP
0.50

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

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

Other links and lift over

dbSNP: rs555260071; hg19: chr14-73718467; API