10-73913343-T-C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002658.6(PLAU):​c.422T>C​(p.Leu141Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.756 in 1,613,776 control chromosomes in the GnomAD database, including 464,486 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 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: 𝑓 0.80 (50108 hom., cov: 31)
  • Exomes 𝑓: 0.75 (414378 hom.)
• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.153914E-6).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.948 is higher than 0.05.

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>C	p.Leu141Pro	missense	Exon 6 of 11	NP_002649.2	P00749-1
	PLAU	NM_001441154.1		c.422T>C	p.Leu141Pro	missense	Exon 7 of 12	NP_001428083.1
	PLAU	NM_001441155.1		c.422T>C	p.Leu141Pro	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>C	p.Leu141Pro	missense	Exon 6 of 11	ENSP00000361850.3	P00749-1
	C10orf55	ENST00000409178.5	TSL:1	n.269-268A>G		intron	N/A
	PLAU	ENST00000894723.1		c.422T>C	p.Leu141Pro	missense	Exon 5 of 10	ENSP00000564782.1

Frequencies

GnomAD3 genomes AF: 0.805 AC: 122342 AN: 152008 Hom.: 50053 Cov.: 31

Gnomad AFR AF: 0.956

Gnomad AMI AF: 0.708

Gnomad AMR AF: 0.772

Gnomad ASJ AF: 0.907

Gnomad EAS AF: 0.651

Gnomad SAS AF: 0.683

Gnomad FIN AF: 0.672

Gnomad MID AF: 0.889

Gnomad NFE AF: 0.756

Gnomad OTH AF: 0.847

GnomAD2 exomes AF: 0.748 AC: 188116 AN: 251376 AF XY: 0.747

Gnomad AFR exome AF: 0.962

Gnomad AMR exome AF: 0.705

Gnomad ASJ exome AF: 0.897

Gnomad EAS exome AF: 0.631

Gnomad FIN exome AF: 0.666

Gnomad NFE exome AF: 0.764

Gnomad OTH exome AF: 0.777

GnomAD4 exome AF: 0.751 AC: 1097234 AN: 1461650 Hom.: 414378 Cov.: 53 AF XY: 0.751 AC XY: 545874 AN XY: 727126

African (AFR) AF: 0.965 AC: 32307 AN: 33478

American (AMR) AF: 0.714 AC: 31905 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.900 AC: 23526 AN: 26136

East Asian (EAS) AF: 0.712 AC: 28252 AN: 39698

South Asian (SAS) AF: 0.701 AC: 60499 AN: 86254

European-Finnish (FIN) AF: 0.673 AC: 35921 AN: 53408

Middle Eastern (MID) AF: 0.908 AC: 5237 AN: 5768

European-Non Finnish (NFE) AF: 0.749 AC: 833006 AN: 1111804

Other (OTH) AF: 0.771 AC: 46581 AN: 60388

GnomAD4 genome AF: 0.805 AC: 122449 AN: 152126 Hom.: 50108 Cov.: 31 AF XY: 0.798 AC XY: 59347 AN XY: 74348

African (AFR) AF: 0.956 AC: 39693 AN: 41516

American (AMR) AF: 0.771 AC: 11775 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.907 AC: 3149 AN: 3472

East Asian (EAS) AF: 0.652 AC: 3358 AN: 5152

South Asian (SAS) AF: 0.683 AC: 3292 AN: 4822

European-Finnish (FIN) AF: 0.672 AC: 7112 AN: 10590

Middle Eastern (MID) AF: 0.891 AC: 262 AN: 294

European-Non Finnish (NFE) AF: 0.756 AC: 51384 AN: 67984

Other (OTH) AF: 0.842 AC: 1781 AN: 2116

Alfa AF: 0.783 Hom.: 164838

Bravo AF: 0.820

TwinsUK AF: 0.752 AC: 2787

ALSPAC AF: 0.726 AC: 2798

ESP6500AA AF: 0.955 AC: 4209

ESP6500EA AF: 0.779 AC: 6699

ExAC AF: 0.754 AC: 91609

Asia WGS AF: 0.672 AC: 2340 AN: 3478

EpiCase AF: 0.781

EpiControl AF: 0.789

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	14
DANN	Benign	0.95
DEOGEN2	Benign	0.032	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.057	N
LIST_S2	Benign	0.044	T
MetaRNN	Benign	0.0000012	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.39
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.25
Sift	Benign	0.11	T
Sift4G	Benign	0.15	T
Polyphen		0.68	P
Vest4		0.13
MPC		0.45
ClinPred		0.044	T
GERP RS		3.1
gMVP		0.86
Mutation Taster		=99/1	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: rs2227564; hg19: chr10-75673101; COSMIC: COSV65640923; COSMIC: COSV65640923;