chr14-73244663-A-G

Variant names:

• chr14-73244663-A-G
• NM_001365906.3:c.74A>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.74A>G​(p.Gln25Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,437,878 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. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q25H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PAPLN NM_001365906.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.19
• Publications: 0 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=0.2808833).

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.74A>G	p.Gln25Arg	missense	Exon 3 of 27	NP_001352835.1	O95428-1
	PAPLN	NM_001365907.2		c.74A>G	p.Gln25Arg	missense	Exon 2 of 26	NP_001352836.1	O95428-5
	PAPLN	NM_173462.4		c.74A>G	p.Gln25Arg	missense	Exon 3 of 26	NP_775733.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAPLN	ENST00000644200.2	MANE Select	c.74A>G	p.Gln25Arg	missense	Exon 3 of 27	ENSP00000495882.2	O95428-1
	PAPLN	ENST00000216658.9	TSL:1	n.74A>G		non_coding_transcript_exon	Exon 3 of 27	ENSP00000216658.5	B5MDP7
	PAPLN-AS1	ENST00000554614.3	TSL:1	n.1077T>C		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1437878 Hom.: 0 Cov.: 30 AF XY: 0.00000281 AC XY: 2 AN XY: 713000

⚠️ 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: 32868

American (AMR) AF: 0.00 AC: 0 AN: 41386

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25608

East Asian (EAS) AF: 0.00 AC: 0 AN: 38144

South Asian (SAS) AF: 0.00 AC: 0 AN: 82142

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51446

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5714

European-Non Finnish (NFE) AF: 0.00000182 AC: 2 AN: 1101118

Other (OTH) AF: 0.00 AC: 0 AN: 59452

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0296732), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.051	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.024	T
Eigen	Benign	0.075
Eigen_PC	Benign	0.021
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.1	L
PhyloP100		2.2
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.14
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.078	T
Polyphen		1.0	D
Vest4		0.22
MutPred		0.21		Gain of MoRF binding (P = 0.0364)
MVP		0.42
MPC		0.24
ClinPred		0.84	D
GERP RS		2.4
Varity_R		0.34
gMVP		0.49
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

hg19: chr14-73711371; COSMIC: COSV99390789; COSMIC: COSV99390789;