Genetic Variant SERPINE1:c.-123+152_-123+153insA (chr7-101126425-T-TA) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is The variant received 2 classification points (ACMG Germline Pathogenicity v2019). PM2

The ENST00000950058.1(SERPINE1):c.-123+152_-123+153insA variant causes a intron change. Note: ENST00000950058.1 is not a MANE Select or MANE Plus Clinical transcript for SERPINE1; the reported annotation may differ from that of the MANE-designated reference transcript for this gene. The variant allele was found at a cumulative frequency of 0.0000132 (AC=2) in the gnomAD database across 151,806 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.00000801. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 0)

Consequence

SERPINE1
ENST00000950058.1 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.386

Publications

83 publications found

Variant links:

Genes affected

SERPINE1 (HGNC:8583): (serpin family E member 1) This gene encodes a member of the serine proteinase inhibitor (serpin) superfamily. This member is the principal inhibitor of tissue plasminogen activator (tPA) and urokinase (uPA), and hence is an inhibitor of fibrinolysis. The protein also functions as a component of innate antiviral immunity. Defects in this gene are the cause of plasminogen activator inhibitor-1 deficiency (PAI-1 deficiency), and high concentrations of the gene product are associated with thrombophilia. [provided by RefSeq, Aug 2020]

SERPINE1 Gene-Disease associations (from GenCC):

congenital plasminogen activator inhibitor type 1 deficiency
Inheritance: AR, SD Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: ClinGen, Ambry Genetics, PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae)

SERPINE1 links:

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new If you want to explore the variant's impact on the transcript ENST00000950058.1, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 2 points.

Show applied only (1)

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AR/unknown gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.00000801 — very rare for AR gene (threshold 0.001) — PM2 moderate.

Variant Effect in Transcripts

Automated classification analysis was done for transcript: ENST00000950058.1. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	SERPINE1 ENST00000950058.1		c.-123+152_-123+153insA	intron	Intron 3 of 11	Prot: ENSP00000620117.1 UniProt: P05121-1

SERPINE1 ENST00000950058.1

HGVSc / HGVSpc.-123+152_-123+153insA

Exon rankIntron 3 of 11

intron

Prot: ENSP00000620117.1UniProt: P05121-1

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 4 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0000132	AC:2	Hom:0	AN:151806	Cov:0
GnomAD4 genome	AF: 0.0000132	AC:2	Hom:0	AN:151806	Cov:0
TOPMed (Bravo) Warning	AF: 0.00000756	AC:2	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:14844	Cov:

Showing 4 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Benign	0.39

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational Scores

Splicing Scores

MaveDB functional evidence ?

Publications

Other links and lift over

MaveDB functional evidence