6-160731787-C-T

Variant names:

• chr6-160731787-C-T
• rs4252128
• NM_000301.5:c.1481C>T
• PLG p.Ala494Val

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:3
• Conservation: PhyloP100: 5.71
• Publications: 28 publications found

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: ClinGen, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• angioedema, hereditary, 4

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000301.5. 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
	PLG	NM_000301.5	MANE Select	c.1481C>T	p.Ala494Val	missense	Exon 12 of 19	NP_000292.1	P00747

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLG	ENST00000308192.14	TSL:1 MANE Select	c.1481C>T	p.Ala494Val	missense	Exon 12 of 19	ENSP00000308938.9	P00747
	PLG	ENST00000872438.1		c.1481C>T	p.Ala494Val	missense	Exon 12 of 21	ENSP00000542497.1
	PLG	ENST00000872435.1		c.1481C>T	p.Ala494Val	missense	Exon 12 of 19	ENSP00000542494.1

Frequencies

GnomAD3 genomes AF: 0.00975 AC: 1482 AN: 152038 Hom.: 20 Cov.: 32

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

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.: 32 AF XY: 0.00469 AC XY: 3407 AN XY: 727108

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: 53 AN: 39700

South Asian (SAS) AF: 0.000371 AC: 32 AN: 86248

European-Finnish (FIN) AF: 0.0000374 AC: 2 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

GnomAD4 genome AF: 0.00972 AC: 1479 AN: 152156 Hom.: 21 Cov.: 32 AF XY: 0.00952 AC XY: 708 AN XY: 74386

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: 8 AN: 5174

South Asian (SAS) AF: 0.00125 AC: 6 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.00351 AC: 239 AN: 68012

Other (OTH) AF: 0.0147 AC: 31 AN: 2112

Alfa AF: 0.00886 Hom.: 38

Bravo AF: 0.0121

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.00551

EpiControl AF: 0.00545

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)
-	1	-	Otitis media, susceptibility to (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0064	T
MetaSVM	Benign	-0.50	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		5.7
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.28
Sift	Uncertain	0.014	D
Sift4G	Benign	0.30	T
Varity_R		0.40
gMVP		0.95
Mutation Taster		=91/9	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs4252128;

hg19: chr6-161152819;

COSMIC: COSV51984505;

COSMIC: COSV51984505;