NM_002659.4:c.721A>G

Variant names:

• chr19-43652258-T-C
• rs759697690
• NM_002659.4:c.721A>G
• PLAUR p.Met241Val

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+2 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 2 classification points (ACMG Germline Pathogenicity v2019). PM2

The NM_002659.4(PLAUR):c.721A>G (p.Met241Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00000372 (AC=6) in the gnomAD database across 1,613,978 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000325. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (★). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.M241T: Uncertain_significance (ClinVar VariationId 3933594, 1 star)

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PLAUR NM_002659.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.53
• Publications: 0 publications found

Genes affected

PLAUR (HGNC:9053): (plasminogen activator, urokinase receptor) This gene encodes the receptor for urokinase plasminogen activator and, given its role in localizing and promoting plasmin formation, likely influences many normal and pathological processes related to cell-surface plasminogen activation and localized degradation of the extracellular matrix. It binds both the proprotein and mature forms of urokinase plasminogen activator and permits the activation of the receptor-bound pro-enzyme by plasmin. The protein lacks transmembrane or cytoplasmic domains and may be anchored to the plasma membrane by a glycosyl-phosphatidylinositol (GPI) moiety following cleavage of the nascent polypeptide near its carboxy-terminus. However, a soluble protein is also produced in some cell types. Alternative splicing results in multiple transcript variants encoding different isoforms. The proprotein experiences several post-translational cleavage reactions that have not yet been fully defined. [provided by RefSeq, Jul 2008]

ENSG00000308028 (HGNC:):

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AR/unknown gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.0000325 — very rare for unknown gene (threshold 0.001) — PM2 moderate.

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_002659.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	PLAUR NM_002659.4	MANE Select	c.721A>G p.Met241Val	missense	Exon 6 of 7	Prot: NP_002650.1 UniProt:
	PLAUR NM_001005377.3		c.586A>G p.Met196Val	missense	Exon 5 of 6	Prot: NP_001005377.1 UniProt:
	PLAUR NM_001005376.3		c.721A>G p.Met241Val	missense	Exon 6 of 7	Prot: NP_001005376.1 UniProt:

PLAUR NM_002659.4

MANE Select

HGVSc / HGVSpc.721A>Gp.Met241Val

Exon rankExon 6 of 7

missense

Prot: NP_002650.1UniProt: Q03405-1

PLAUR NM_001005377.3

HGVSc / HGVSpc.586A>Gp.Met196Val

Exon rankExon 5 of 6

missense

Prot: NP_001005377.1UniProt: Q03405-3

PLAUR NM_001005376.3

HGVSc / HGVSpc.721A>Gp.Met241Val

Exon rankExon 6 of 7

missense

Prot: NP_001005376.1UniProt: Q03405-2

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	PLAUR ENST00000340093.8	TSL:1MANE Select	c.721A>G p.Met241Val	missense	Exon 6 of 7	Prot: ENSP00000339328.3 UniProt:
	PLAUR ENST00000221264.8	TSL:1	c.586A>G p.Met196Val	missense	Exon 5 of 6	Prot: ENSP00000221264.3 UniProt:
	PLAUR ENST00000339082.7	TSL:1	c.721A>G p.Met241Val	missense	Exon 6 of 7	Prot: ENSP00000342049.2 UniProt:

PLAUR ENST00000340093.8

TSL:1MANE Select

HGVSc / HGVSpc.721A>Gp.Met241Val

Exon rankExon 6 of 7

missense

Prot: ENSP00000339328.3UniProt: Q03405-1

PLAUR ENST00000221264.8

TSL:1

HGVSc / HGVSpc.586A>Gp.Met196Val

Exon rankExon 5 of 6

missense

Prot: ENSP00000221264.3UniProt: Q03405-3

PLAUR ENST00000339082.7

TSL:1

HGVSc / HGVSpc.721A>Gp.Met241Val

Exon rankExon 6 of 7

missense

Prot: ENSP00000342049.2UniProt: Q03405-2

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0000263	AC:4	Hom:0	AN:152118	Cov:32
GnomAD2 exomes	AF: 0.00000398	AC:1	Hom:	AN:251478	Cov:
GnomAD4 exome	AF: 0.00000137	AC:2	Hom:0	AN:1461860	Cov:31
GnomAD4 genome	AF: 0.0000263	AC:4	Hom:0	AN:152118	Cov:32
TOPMed (Bravo)	AF: 0.0000151	AC:4	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000602	AC:2	Hom:0	AN:33200	Cov:

Showing 6 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.00	0	77660	0.0000144	2	139320

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	25
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Uncertain	0.027	T
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Benign	0.68	D
FuncVEP CTI	Pathogenic	0.86
GPN-Star LLR	N/A	-6.3
GPN-Star score	N/A	6.3
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Uncertain	0.12	D
Mutation Taster	N/A	57/43	polymorphism
MutationAssessor	Benign	1.8	L
PhyloP100	Benign	3.5
popEVE	Benign	-3.5
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0050	D
Sift4G	Pathogenic	0.0	D
Varity_R	N/A	0.57
VESM-3B	Benign	-8.3

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs759697690;

hg19: chr19-44156410;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar