NM_000301.5:c.1481C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000301.5(PLG):c.1481C>T(p.Ala494Val) variant causes a missense change. The variant allele was found at a frequency of 0.00524 in 1,613,724 control chromosomes in the GnomAD database, including 121 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A494E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0097 ( 21 hom., cov: 32)

Exomes 𝑓: 0.0048 ( 100 hom. )

Consequence

PLG
NM_000301.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts U:1B:2

Conservation

PhyloP100: 5.71

Publications

28 publications found

Variant links:

Genes affected

PLG (HGNC:9071): (plasminogen) The plasminogen protein encoded by this gene is a serine protease that circulates in blood plasma as an inactive zymogen and is converted to the active protease, plasmin, by several plasminogen activators such as tissue plasminogen activator (tPA), urokinase plasminogen activator (uPA), kallikrein, and factor XII (Hageman factor). The conversion of plasminogen to plasmin involves the cleavage of the peptide bond between Arg-561 and Val-562. Plasmin cleavage also releases the angiostatin protein which inhibits angiogenesis. Plasmin degrades many blood plasma proteins, including fibrin-containing blood clots. As a serine protease, plasmin cleaves many products in addition to fibrin such as fibronectin, thrombospondin, laminin, and von Willebrand factor. Plasmin is inactivated by proteins such as alpha-2-macroglobulin and alpha-2-antiplasmin in addition to inhibitors of the various plasminogen activators. Plasminogen also interacts with plasminogen receptors which results in the retention of plasmin on cell surfaces and in plasmin-induced cell signaling. The localization of plasminogen on cell surfaces plays a role in the degradation of extracellular matrices, cell migration, inflamation, wound healing, oncogenesis, metastasis, myogenesis, muscle regeneration, neurite outgrowth, and fibrinolysis. This protein may also play a role in acute respiratory distress syndrome (ARDS) which, in part, is caused by enhanced clot formation and the suppression of fibrinolysis. Compared to other mammals, the cluster of plasminogen-like genes to which this gene belongs has been rearranged in catarrhine primates. [provided by RefSeq, May 2020]

PLG Gene-Disease associations (from GenCC):

hypoplasminogenemia
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
angioedema, hereditary, 4
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

PLG links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006421864).

BP6

Variant 6-160731787-C-T is Benign according to our data. Variant chr6-160731787-C-T is described in ClinVar as Benign. ClinVar VariationId is 692204.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00972 (1479/152156) while in subpopulation AMR AF = 0.0189 (289/15282). AF 95% confidence interval is 0.0171. There are 21 homozygotes in GnomAd4. There are 708 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 21 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLG	NM_000301.5 link	c.1481C>T	p.Ala494Val	missense_variant	Exon 12 of 19	ENST00000308192.14	NP_000292.1	P00747

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLG	ENST00000308192.14 link	c.1481C>T	p.Ala494Val	missense_variant	Exon 12 of 19	1	NM_000301.5	ENSP00000308938.9		P00747

Frequencies

GnomAD3 genomes

AF:

0.00975

AC:

1482

AN:

152038

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0165

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0191

Gnomad ASJ

AF:

0.0606

Gnomad EAS

AF:

0.00154

Gnomad SAS

AF:

0.00125

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.00351

Gnomad OTH

AF:

0.0148

GnomAD2 exomes

AF:

0.00985

AC:

2477

AN:

251394

AF XY:

0.00875

show subpopulations

Gnomad AFR exome

AF:

0.0168

Gnomad AMR exome

AF:

0.0301

Gnomad ASJ exome

AF:

0.0559

Gnomad EAS exome

AF:

0.000870

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00420

Gnomad OTH exome

AF:

0.0160

GnomAD4 exome

AF:

0.00478

AC:

6983

AN:

1461568

Hom.:

100

Cov.:

AF XY:

0.00469

AC XY:

3407

AN XY:

727108

show subpopulations

African (AFR)

AF:

0.0161

AC:

539

AN:

33472

American (AMR)

AF:

0.0294

AC:

1314

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0588

AC:

1537

AN:

26130

East Asian (EAS)

AF:

0.00134

AC:

AN:

39700

South Asian (SAS)

AF:

0.000371

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.0000374

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.0274

AC:

158

AN:

5768

European-Non Finnish (NFE)

AF:

0.00235

AC:

2618

AN:

1111728

Other (OTH)

AF:

0.0121

AC:

730

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

409

818

1226

1635

2044

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

130

260

390

520

650

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00972

AC:

1479

AN:

152156

Hom.:

Cov.:

AF XY:

0.00952

AC XY:

708

AN XY:

74386

show subpopulations

African (AFR)

AF:

0.0165

AC:

683

AN:

41506

American (AMR)

AF:

0.0189

AC:

289

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.0606

AC:

210

AN:

3468

East Asian (EAS)

AF:

0.00155

AC:

AN:

5174

South Asian (SAS)

AF:

0.00125

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10586

Middle Eastern (MID)

AF:

0.0442

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00351

AC:

239

AN:

68012

Other (OTH)

AF:

0.0147

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

138

207

276

345

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00886

Hom.:

Bravo

AF:

0.0121

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.0136

AC:

ESP6500EA

AF:

0.00593

AC:

ExAC

AF:

0.00815

AC:

990

Asia WGS

AF:

0.00606

AC:

AN:

3478

EpiCase

AF:

0.00551

EpiControl

AF:

0.00545

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Feb 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PLG: BP4, BS1, BS2 -

Otitis media, susceptibility to

Uncertain:1

Jul 26, 2019

Santos-Cortez Lab, University of Colorado School of Medicine

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.42

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.78

LIST_S2

Uncertain

0.87

MetaRNN

Benign

0.0064

MetaSVM

Benign

-0.50

MutationAssessor

Uncertain

2.8

PhyloP100

5.7

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-2.4

REVEL

Benign

0.28

Sift

Uncertain

0.014

Sift4G

Benign

0.30

Polyphen

0.99

Vest4

0.32

MVP

0.88

MPC

0.76

ClinPred

0.051

GERP RS

4.5

Varity_R

0.40

gMVP

0.95

Mutation Taster

=91/9

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over