10-73911531-C-T

Position:

• chr10-73911531-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_002658.6(PLAU):​c.-25C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00918 in 1,609,382 control chromosomes in the GnomAD database, including 97 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0059 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0095 (94 hom.)
• Consequence: PLAU NM_002658.6 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.455

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 10-73911531-C-T is Benign according to our data. Variant chr10-73911531-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 300736.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 898 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLAU	NM_002658.6	c.-25C>T		5_prime_UTR_variant	2/11	ENST00000372764.4
C10orf55	NR_160938.1	n.951G>A		non_coding_transcript_exon_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLAU	ENST00000372764.4	c.-25C>T		5_prime_UTR_variant	2/11	1	NM_002658.6	P1
C10orf55	ENST00000409178.5	n.951G>A		non_coding_transcript_exon_variant	5/5	1

Frequencies

GnomAD3 genomes AF: 0.00590 AC: 898 AN: 152228 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00186

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00406

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.000847

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0104

Gnomad OTH AF: 0.00718

GnomAD3 exomes AF: 0.00595 AC: 1446 AN: 242990 Hom.: 9 AF XY: 0.00604 AC XY: 798 AN XY: 132102

Gnomad AFR exome AF: 0.00202

Gnomad AMR exome AF: 0.00472

Gnomad ASJ exome AF: 0.00937

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00159

Gnomad FIN exome AF: 0.00122

Gnomad NFE exome AF: 0.00953

Gnomad OTH exome AF: 0.00734

GnomAD4 exome AF: 0.00952 AC: 13878 AN: 1457036 Hom.: 94 Cov.: 32 AF XY: 0.00923 AC XY: 6692 AN XY: 724892

Gnomad4 AFR exome AF: 0.00134

Gnomad4 AMR exome AF: 0.00496

Gnomad4 ASJ exome AF: 0.00752

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00141

Gnomad4 FIN exome AF: 0.00126

Gnomad4 NFE exome AF: 0.0115

Gnomad4 OTH exome AF: 0.00756

GnomAD4 genome AF: 0.00589 AC: 898 AN: 152346 Hom.: 3 Cov.: 32 AF XY: 0.00528 AC XY: 393 AN XY: 74500

Gnomad4 AFR AF: 0.00185

Gnomad4 AMR AF: 0.00405

Gnomad4 ASJ AF: 0.00634

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.000847

Gnomad4 NFE AF: 0.0104

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00870 Hom.: 4

Bravo AF: 0.00646

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	C10orf55: BS2; PLAU: BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Quebec platelet disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	6.8
DANN	Benign	0.81

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: rs2227579; hg19: chr10-75671289;