14-73246112-T-C

Variant names:

• chr14-73246112-T-C
• rs780971024
• NM_001365906.3:c.271T>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001365906.3(PAPLN):​c.271T>C​(p.Cys91Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000209 in 1,436,776 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PAPLN NM_001365906.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.88

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-AS1 (HGNC:55451): (PAPLN antisense RNA 1)

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.956

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAPLN	NM_001365906.3	c.271T>C	p.Cys91Arg	missense_variant	Exon 5 of 27	ENST00000644200.2	NP_001352835.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAPLN	ENST00000644200.2	c.271T>C	p.Cys91Arg	missense_variant	Exon 5 of 27		NM_001365906.3	ENSP00000495882.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000209 AC: 3 AN: 1436776 Hom.: 0 Cov.: 31 AF XY: 0.00000280 AC XY: 2 AN XY: 714144

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000712

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000830 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 01, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.271T>C (p.C91R) alteration is located in exon 5 (coding exon 4) of the PAPLN gene. This alteration results from a T to C substitution at nucleotide position 271, causing the cysteine (C) at amino acid position 91 to be replaced by an arginine (R). 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	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.42	T;.;T;.
Eigen	Pathogenic	0.81
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D;D;.;D
M_CAP	Benign	0.053	D
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	4.5	H;H;H;H
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-11	.;D;D;D
REVEL	Uncertain	0.51
Sift	Pathogenic	0.0	.;D;D;D
Sift4G	Uncertain	0.0020	.;D;D;D
Polyphen		0.99	D;D;D;D
Vest4		0.94, 0.93, 0.95
MutPred		0.78		Gain of MoRF binding (P = 0.0609);Gain of MoRF binding (P = 0.0609);Gain of MoRF binding (P = 0.0609);Gain of MoRF binding (P = 0.0609);
MVP		0.46
MPC		0.94
ClinPred		1.0	D
GERP RS		4.1
Varity_R		0.95
gMVP		0.96

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

Other links and lift over

dbSNP: rs780971024; hg19: chr14-73712820;