NM_000301.5:c.49+66T>C

Variant names:

• chr6-160702419-T-C
• rs4252185
• NM_000301.5:c.49+66T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000301.5(PLG):​c.49+66T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0752 in 1,389,948 control chromosomes in the GnomAD database, including 4,883 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.056 (351 hom., cov: 33)
  • Exomes 𝑓: 0.078 (4532 hom.)
• Consequence: PLG NM_000301.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.165
• 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, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• angioedema, hereditary, 4

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

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 6-160702419-T-C is Benign according to our data. Variant chr6-160702419-T-C is described in ClinVar as Benign. ClinVar VariationId is 1221071.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0876 is higher than 0.05.

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.49+66T>C		intron	N/A	NP_000292.1	P00747
	PLG	NM_001168338.1		c.49+66T>C		intron	N/A	NP_001161810.1	Q5TEH5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLG	ENST00000308192.14	TSL:1 MANE Select	c.49+66T>C		intron	N/A	ENSP00000308938.9	P00747
	PLG	ENST00000366924.6	TSL:1	c.49+66T>C		intron	N/A	ENSP00000355891.2	Q5TEH5
	PLG	ENST00000872438.1		c.49+66T>C		intron	N/A	ENSP00000542497.1

Frequencies

GnomAD3 genomes AF: 0.0562 AC: 8556 AN: 152190 Hom.: 351 Cov.: 33

Gnomad AFR AF: 0.0218

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.0475

Gnomad ASJ AF: 0.0311

Gnomad EAS AF: 0.00212

Gnomad SAS AF: 0.00912

Gnomad FIN AF: 0.0507

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0895

Gnomad OTH AF: 0.0501

GnomAD4 exome AF: 0.0775 AC: 95937 AN: 1237640 Hom.: 4532 AF XY: 0.0753 AC XY: 46982 AN XY: 623690

African (AFR) AF: 0.0180 AC: 493 AN: 27422

American (AMR) AF: 0.0314 AC: 1239 AN: 39462

Ashkenazi Jewish (ASJ) AF: 0.0274 AC: 652 AN: 23812

East Asian (EAS) AF: 0.000583 AC: 22 AN: 37764

South Asian (SAS) AF: 0.0116 AC: 878 AN: 75484

European-Finnish (FIN) AF: 0.0597 AC: 2985 AN: 50034

Middle Eastern (MID) AF: 0.0171 AC: 62 AN: 3624

European-Non Finnish (NFE) AF: 0.0931 AC: 86318 AN: 927484

Other (OTH) AF: 0.0626 AC: 3288 AN: 52554

GnomAD4 genome AF: 0.0562 AC: 8555 AN: 152308 Hom.: 351 Cov.: 33 AF XY: 0.0519 AC XY: 3868 AN XY: 74472

African (AFR) AF: 0.0218 AC: 907 AN: 41580

American (AMR) AF: 0.0473 AC: 724 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0311 AC: 108 AN: 3468

East Asian (EAS) AF: 0.00212 AC: 11 AN: 5186

South Asian (SAS) AF: 0.00892 AC: 43 AN: 4822

European-Finnish (FIN) AF: 0.0507 AC: 538 AN: 10612

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0895 AC: 6090 AN: 68024

Other (OTH) AF: 0.0496 AC: 105 AN: 2116

Alfa AF: 0.0685 Hom.: 64

Bravo AF: 0.0541

Asia WGS AF: 0.00982 AC: 35 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.73
DANN	Benign	0.78
PhyloP100		-0.17
PromoterAI		0.0098	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

dbSNP: rs4252185; hg19: chr6-161123451; COSMIC: COSV51986024; COSMIC: COSV51986024;