14-73246140-A-G

Variant names:

• chr14-73246140-A-G
• rs368511037
• NM_001365906.3:c.299A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001365906.3(PAPLN):​c.299A>G​(p.Gln100Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000378 in 1,588,448 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q100L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PAPLN NM_001365906.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.36
• Publications: 2 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36383897).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAPLN	NM_001365906.3	MANE Select	c.299A>G	p.Gln100Arg	missense	Exon 5 of 27	NP_001352835.1	O95428-1
	PAPLN	NM_001365907.2		c.299A>G	p.Gln100Arg	missense	Exon 4 of 26	NP_001352836.1	O95428-5
	PAPLN	NM_173462.4		c.299A>G	p.Gln100Arg	missense	Exon 5 of 26	NP_775733.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAPLN	ENST00000644200.2	MANE Select	c.299A>G	p.Gln100Arg	missense	Exon 5 of 27	ENSP00000495882.2	O95428-1
	PAPLN	ENST00000216658.9	TSL:1	n.299A>G		non_coding_transcript_exon	Exon 5 of 27	ENSP00000216658.5	B5MDP7
	PAPLN	ENST00000555123.5	TSL:1	n.299A>G		non_coding_transcript_exon	Exon 5 of 24	ENSP00000452455.1	G3V5P6

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 151912 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000209 AC: 3 AN: 1436536 Hom.: 0 Cov.: 31 AF XY: 0.00000280 AC XY: 2 AN XY: 714444

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30556

American (AMR) AF: 0.0000245 AC: 1 AN: 40872

Ashkenazi Jewish (ASJ) AF: 0.0000398 AC: 1 AN: 25148

East Asian (EAS) AF: 0.00 AC: 0 AN: 37092

South Asian (SAS) AF: 0.0000119 AC: 1 AN: 83704

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51730

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5684

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1102576

Other (OTH) AF: 0.00 AC: 0 AN: 59174

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 151912 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74204

African (AFR) AF: 0.0000484 AC: 2 AN: 41318

American (AMR) AF: 0.0000655 AC: 1 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67976

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Benign	0.024	T
Eigen	Benign	0.00046
Eigen_PC	Benign	-0.014
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.6	L
PhyloP100		7.4
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.28
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.058	T
Polyphen		0.95	P
Vest4		0.56
MVP		0.42
MPC		0.63
ClinPred		0.94	D
GERP RS		3.1
Varity_R		0.17
gMVP		0.52
Mutation Taster		=85/15	polymorphism

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

Other links and lift over

dbSNP: rs368511037; hg19: chr14-73712848;