chr14-73251697-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001365906.3(PAPLN):ā€‹c.704A>Gā€‹(p.Asn235Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,461,000 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 0.0000055 ( 0 hom. )

Consequence

PAPLN
NM_001365906.3 missense

Scores

2
11
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.40
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PAPLNNM_001365906.3 linkuse as main transcriptc.704A>G p.Asn235Ser 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.704A>G p.Asn235Ser missense_variant 9/27 NM_001365906.3 ENSP00000495882 P1O95428-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000548
AC:
8
AN:
1461000
Hom.:
0
Cov.:
33
AF XY:
0.00000275
AC XY:
2
AN XY:
726834
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.0000766
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000540
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
Alfa
AF:
0.0000329
Hom.:
0
Bravo
AF:
0.00000378
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

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 GeneticsApr 04, 2024The c.623A>G (p.N208S) alteration is located in exon 8 (coding exon 7) of the PAPLN gene. This alteration results from a A to G substitution at nucleotide position 623, causing the asparagine (N) at amino acid position 208 to be replaced by a serine (S). 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
0.31
BayesDel_addAF
Uncertain
0.069
D
BayesDel_noAF
Benign
-0.14
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.17
T;.;T;.
Eigen
Uncertain
0.56
Eigen_PC
Uncertain
0.51
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Uncertain
0.93
D;D;.;D
M_CAP
Benign
0.047
D
MetaRNN
Uncertain
0.70
D;D;D;D
MetaSVM
Uncertain
0.095
D
MutationAssessor
Pathogenic
4.0
H;.;H;H
MutationTaster
Benign
1.0
D;D;D;D;D
PrimateAI
Benign
0.47
T
PROVEAN
Pathogenic
-4.7
.;D;D;D
REVEL
Uncertain
0.39
Sift
Uncertain
0.0090
.;D;D;D
Sift4G
Uncertain
0.037
.;D;D;D
Polyphen
0.63
P;D;P;P
Vest4
0.78, 0.73, 0.69
MVP
0.71
MPC
0.28
ClinPred
0.96
D
GERP RS
4.5
Varity_R
0.63
gMVP
0.74

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: rs1454679379; hg19: chr14-73718405; COSMIC: COSV53716935; COSMIC: COSV53716935; API