Genetic Variant PLAG1:p.Asp385Glu (chr8-56166591-A-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_002655.3(PLAG1):c.1155T>G(p.Asp385Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,702 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PLAG1
NM_002655.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.0720

Publications

0 publications found

Variant links:

Genes affected

PLAG1 (HGNC:9045): (PLAG1 zinc finger) Pleomorphic adenoma gene 1 encodes a zinc finger protein with 2 putative nuclear localization signals. PLAG1, which is developmentally regulated, has been shown to be consistently rearranged in pleomorphic adenomas of the salivary glands. PLAG1 is activated by the reciprocal chromosomal translocations involving 8q12 in a subset of salivary gland pleomorphic adenomas. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

PLAG1 Gene-Disease associations (from GenCC):

silver-russell syndrome 4
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

PLAG1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.054505497).

BP6

Variant 8-56166591-A-C is Benign according to our data. Variant chr8-56166591-A-C is described in ClinVar as Likely_benign. ClinVar VariationId is 2333592.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002655.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PLAG1	NM_002655.3	MANE Select	c.1155T>G	p.Asp385Glu	missense	Exon 5 of 5	NP_002646.2	Q6DJT9-1
PLAG1	NM_001114634.2		c.1155T>G	p.Asp385Glu	missense	Exon 4 of 4	NP_001108106.1	Q6DJT9-1
PLAG1	NM_001114635.2		c.909T>G	p.Asp303Glu	missense	Exon 3 of 3	NP_001108107.1	Q6DJT9-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PLAG1	ENST00000316981.8	TSL:1 MANE Select	c.1155T>G	p.Asp385Glu	missense	Exon 5 of 5	ENSP00000325546.3	Q6DJT9-1
PLAG1	ENST00000429357.2	TSL:1	c.1155T>G	p.Asp385Glu	missense	Exon 4 of 4	ENSP00000416537.2	Q6DJT9-1
PLAG1	ENST00000522009.1	TSL:1	n.1606T>G		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461702

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727152

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26108

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86238

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111920

Other (OTH)

AF:

0.0000331

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.82

CADD

Benign

5.1

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.059

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.72

FATHMM_MKL

Benign

0.43

LIST_S2

Benign

0.67

M_CAP

Benign

0.0026

MetaRNN

Benign

0.055

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-0.20

PhyloP100

-0.072

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.13

REVEL

Benign

0.067

Sift

Benign

0.41

Sift4G

Benign

0.74

Polyphen

0.0

Vest4

0.045

MutPred

0.28

Gain of catalytic residue at D385 (P = 0.2606)

MVP

0.11

MPC

0.52

ClinPred

0.23

GERP RS

-4.1

Varity_R

0.061

gMVP

0.068

Mutation Taster

=81/19

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over