rs2227564

Positions:

• chr10-73913343-T-A
• chr10-73913343-T-C
• chr10-73913343-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002658.6(PLAU):​c.422T>A​(p.Leu141Gln) 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. 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L141P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PLAU NM_002658.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.394

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06980035).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLAU	NM_002658.6	c.422T>A	p.Leu141Gln	missense_variant	6/11	ENST00000372764.4	NP_002649.2
C10orf55	NR_160938.1	n.269-268A>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLAU	ENST00000372764.4	c.422T>A	p.Leu141Gln	missense_variant	6/11	1	NM_002658.6	ENSP00000361850	P1
C10orf55	ENST00000409178.5	n.269-268A>T		intron_variant, non_coding_transcript_variant		1
PLAU	ENST00000446342.5	c.371T>A	p.Leu124Gln	missense_variant	5/10	2		ENSP00000388474
PLAU	ENST00000494287.1	n.497T>A		non_coding_transcript_exon_variant	5/6	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1461870 Hom.: 0 Cov.: 53 AF XY: 0.00 AC XY: 0 AN XY: 727234

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.050
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	6.0
DANN	Benign	0.73
DEOGEN2	Benign	0.021	T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0029	N
LIST_S2	Benign	0.094	T;.
M_CAP	Benign	0.0089	T
MetaRNN	Benign	0.070	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.45	N;N
REVEL	Benign	0.092
Sift	Benign	0.37	T;T
Sift4G	Benign	0.50	T;T
Polyphen		0.0010	B;.
Vest4		0.15
MutPred		0.61		Gain of disorder (P = 0.0436);.;
MVP		0.26
MPC		0.29
ClinPred		0.19	T
GERP RS		3.1
gMVP		0.66

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

Publications

LitVar

Other links and lift over

dbSNP: rs2227564; hg19: chr10-75673101;