chr10-73913343-T-C

Position:

• chr10-73913343-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 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. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in Lovd as Benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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

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:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.153914E-6).
• BP6: Variant 10-73913343-T-C is Benign according to our data. Variant chr10-73913343-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.948 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLAU	NM_002658.6	c.422T>C	p.Leu141Pro	missense_variant	6/11	ENST00000372764.4	NP_002649.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLAU	ENST00000372764.4	c.422T>C	p.Leu141Pro	missense_variant	6/11	1	NM_002658.6	ENSP00000361850.3
C10orf55	ENST00000409178.5	n.269-268A>G		intron_variant		1
PLAU	ENST00000446342.5	c.371T>C	p.Leu124Pro	missense_variant	5/10	2		ENSP00000388474.1
PLAU	ENST00000494287.1	n.497T>C		non_coding_transcript_exon_variant	5/6	2

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

GnomAD3 exomes AF: 0.748 AC: 188116 AN: 251376 Hom.: 71513 AF XY: 0.747 AC XY: 101475 AN XY: 135842

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 SAS exome AF: 0.701

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

Gnomad4 AFR exome AF: 0.965

Gnomad4 AMR exome AF: 0.714

Gnomad4 ASJ exome AF: 0.900

Gnomad4 EAS exome AF: 0.712

Gnomad4 SAS exome AF: 0.701

Gnomad4 FIN exome AF: 0.673

Gnomad4 NFE exome AF: 0.749

Gnomad4 OTH exome AF: 0.771

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

Gnomad4 AFR AF: 0.956

Gnomad4 AMR AF: 0.771

Gnomad4 ASJ AF: 0.907

Gnomad4 EAS AF: 0.652

Gnomad4 SAS AF: 0.683

Gnomad4 FIN AF: 0.672

Gnomad4 NFE AF: 0.756

Gnomad4 OTH AF: 0.842

Alfa AF: 0.782 Hom.: 77478

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 v4.3

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;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-2.1	N;N
REVEL	Benign	0.25
Sift	Benign	0.11	T;T
Sift4G	Benign	0.15	T;T
Polyphen		0.68	P;.
Vest4		0.13
MPC		0.45
ClinPred		0.044	T
GERP RS		3.1
gMVP		0.86

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; COSMIC: COSV65640923; COSMIC: COSV65640923;