Genetic Variant PLAGL2:p.Phe414Leu (chr20-32196701-G-C) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_002657.3(PLAGL2):c.1242C>G(p.Phe414Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000394 in 152,210 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PLAGL2
NM_002657.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.132

Variant links:

Genes affected

PLAGL2 (HGNC:9047): (PLAG1 like zinc finger 2) Pleiomorphic adenoma gene-like 2 is a zinc-finger protein that recognizes DNA and/or RNA. [provided by RefSeq, Jul 2008]

PLAGL2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.24901813).

BS2

High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLAGL2	NM_002657.3 link	c.1242C>G	p.Phe414Leu	missense_variant	Exon 3 of 3	ENST00000246229.5	NP_002648.1	Q9UPG8
PLAGL2	XM_005260436.4 link	c.1242C>G	p.Phe414Leu	missense_variant	Exon 3 of 3		XP_005260493.1	Q9UPG8
PLAGL2	XM_011528864.3 link	c.1242C>G	p.Phe414Leu	missense_variant	Exon 3 of 3		XP_011527166.1	Q9UPG8
PLAGL2	XM_047440200.1 link	c.1242C>G	p.Phe414Leu	missense_variant	Exon 3 of 3		XP_047296156.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLAGL2	ENST00000246229.5 link	c.1242C>G	p.Phe414Leu	missense_variant	Exon 3 of 3	1	NM_002657.3	ENSP00000246229.4		Q9UPG8

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000485

AC:

AN:

206274

Hom.:

AF XY:

0.00

AC XY:

AN XY:

109186

show subpopulations

Gnomad AFR exome

AF:

0.0000636

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

7.11e-7

AC:

AN:

1406278

Hom.:

Cov.:

AF XY:

0.00000144

AC XY:

AN XY:

693042

show subpopulations

Gnomad4 AFR exome

AF:

0.0000312

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.000145

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000378

ExAC

AF:

0.00000826

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 11, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1242C>G (p.F414L) alteration is located in exon 3 (coding exon 2) of the PLAGL2 gene. This alteration results from a C to G substitution at nucleotide position 1242, causing the phenylalanine (F) at amino acid position 414 to be replaced by a leucine (L). 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

0.88

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.080

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.36

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.80

M_CAP

Benign

0.0085

MetaRNN

Benign

0.25

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.4

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

0.20

REVEL

Benign

0.12

Sift

Benign

0.66

Sift4G

Benign

1.0

Polyphen

0.048

Vest4

0.79

MutPred

0.27

Loss of catalytic residue at F414 (P = 0.0195);

MVP

0.23

MPC

1.6

ClinPred

0.084

GERP RS

1.8

Varity_R

0.092

gMVP

0.30

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over