10-73911531-C-T

Variant names:

• chr10-73911531-C-T
• rs2227579
• NM_002658.6:c.-25C>T

Variant summary

Our verdict is Benign. The variant received -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 premature start codon gain 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_premature_start_codon_gain
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.455
• Publications: 2 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 -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 Benign/Likely_benign. ClinVar VariationId is 300736.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 898 AD gene.

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.-25C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 11	NP_002649.2	P00749-1
	PLAU	NM_002658.6	MANE Select	c.-25C>T		5_prime_UTR	Exon 2 of 11	NP_002649.2	P00749-1
	PLAU	NM_001441154.1		c.-25C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 12	NP_001428083.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLAU	ENST00000372764.4	TSL:1 MANE Select	c.-25C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 11	ENSP00000361850.3	P00749-1
	PLAU	ENST00000372764.4	TSL:1 MANE Select	c.-25C>T		5_prime_UTR	Exon 2 of 11	ENSP00000361850.3	P00749-1
	C10orf55	ENST00000409178.5	TSL:1	n.951G>A		non_coding_transcript_exon	Exon 5 of 5

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

GnomAD2 exomes AF: 0.00595 AC: 1446 AN: 242990 AF XY: 0.00604

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 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

African (AFR) AF: 0.00134 AC: 45 AN: 33464

American (AMR) AF: 0.00496 AC: 221 AN: 44562

Ashkenazi Jewish (ASJ) AF: 0.00752 AC: 196 AN: 26078

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39680

South Asian (SAS) AF: 0.00141 AC: 121 AN: 85878

European-Finnish (FIN) AF: 0.00126 AC: 63 AN: 49822

Middle Eastern (MID) AF: 0.00107 AC: 6 AN: 5626

European-Non Finnish (NFE) AF: 0.0115 AC: 12769 AN: 1111600

Other (OTH) AF: 0.00756 AC: 456 AN: 60326

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

African (AFR) AF: 0.00185 AC: 77 AN: 41582

American (AMR) AF: 0.00405 AC: 62 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4826

European-Finnish (FIN) AF: 0.000847 AC: 9 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0104 AC: 706 AN: 68028

Other (OTH) AF: 0.00710 AC: 15 AN: 2112

Alfa AF: 0.00870 Hom.: 4

Bravo AF: 0.00646

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Quebec platelet disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	6.8
DANN	Benign	0.81
PhyloP100		-0.46
PromoterAI		-0.088	Neutral
Mutation Taster		=300/0	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: rs2227579; hg19: chr10-75671289;