chr10-73913343-T-G

Variant names:

• chr10-73913343-T-G
• rs2227564
• NM_002658.6:c.422T>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002658.6(PLAU):​c.422T>G​(p.Leu141Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L141L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PLAU NM_002658.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.394
• Publications: 153 publications found

Genes affected

PLAU (HGNC:9052): (plasminogen activator, urokinase) This gene encodes a secreted serine protease that converts plasminogen to plasmin. The encoded preproprotein is proteolytically processed to generate A and B polypeptide chains. These chains associate via a single disulfide bond to form the catalytically inactive high molecular weight urokinase-type plasminogen activator (HMW-uPA). HMW-uPA can be further processed into the catalytically active low molecular weight urokinase-type plasminogen activator (LMW-uPA). This low molecular weight form does not bind to the urokinase-type plasminogen activator receptor. Mutations in this gene may be associated with Quebec platelet disorder and late-onset Alzheimer's disease. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed. [provided by RefSeq, Jan 2016]

C10orf55 (HGNC:31008): (chromosome 10 putative open reading frame 55) Enables identical protein binding activity. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21227935).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002658.6. 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
	PLAU	NM_002658.6	MANE Select	c.422T>G	p.Leu141Arg	missense	Exon 6 of 11	NP_002649.2	P00749-1
	PLAU	NM_001441154.1		c.422T>G	p.Leu141Arg	missense	Exon 7 of 12	NP_001428083.1
	PLAU	NM_001441155.1		c.422T>G	p.Leu141Arg	missense	Exon 6 of 11	NP_001428084.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLAU	ENST00000372764.4	TSL:1 MANE Select	c.422T>G	p.Leu141Arg	missense	Exon 6 of 11	ENSP00000361850.3	P00749-1
	C10orf55	ENST00000409178.5	TSL:1	n.269-268A>C		intron	N/A
	PLAU	ENST00000894723.1		c.422T>G	p.Leu141Arg	missense	Exon 5 of 10	ENSP00000564782.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 53

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	12
DANN	Benign	0.89
DEOGEN2	Benign	0.029	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.11	T
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.89	T
PhyloP100		0.39
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.13
Sift	Benign	0.064	T
Sift4G	Benign	0.25	T
Polyphen		0.34	B
Vest4		0.18
MutPred		0.67		Gain of MoRF binding (P = 0.0119)
MVP		0.40
MPC		0.41
ClinPred		0.25	T
GERP RS		3.1
gMVP		0.78
Mutation Taster		=97/3	polymorphism

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: rs2227564; hg19: chr10-75673101;