rs6090

chr7-101128442-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000602.5(SERPINE1):c.49G>A(p.Val17Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0171 in 1,614,080 control chromosomes in the GnomAD database, including 512 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.033 (118 hom., cov: 32)
  • Exomes 𝑓: 0.015 (394 hom.)
• Consequence: SERPINE1 NM_000602.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.62

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0027550757).
• BP6: Variant 7-101128442-G-A is Benign according to our data. Variant chr7-101128442-G-A is described in ClinVar as [Benign]. Clinvar id is 358307.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-101128442-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.061 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPINE1	NM_000602.5	c.49G>A	p.Val17Ile	missense_variant	2/9	ENST00000223095.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINE1	ENST00000223095.5	c.49G>A	p.Val17Ile	missense_variant	2/9	1	NM_000602.5	P1

Frequencies

GnomAD3 genomes AF: 0.0327 AC: 4978 AN: 152130 Hom.: 118 Cov.: 32

Gnomad AFR AF: 0.0631

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0313

Gnomad ASJ AF: 0.0213

Gnomad EAS AF: 0.0486

Gnomad SAS AF: 0.0213

Gnomad FIN AF: 0.0573

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0112

Gnomad OTH AF: 0.0374

GnomAD3 exomes AF: 0.0287 AC: 7211 AN: 251170 Hom.: 192 AF XY: 0.0261 AC XY: 3550 AN XY: 135756

Gnomad AFR exome AF: 0.0647

Gnomad AMR exome AF: 0.0530

Gnomad ASJ exome AF: 0.0175

Gnomad EAS exome AF: 0.0512

Gnomad SAS exome AF: 0.0154

Gnomad FIN exome AF: 0.0598

Gnomad NFE exome AF: 0.0113

Gnomad OTH exome AF: 0.0266

GnomAD4 exome AF: 0.0154 AC: 22541 AN: 1461832 Hom.: 394 Cov.: 33 AF XY: 0.0151 AC XY: 10982 AN XY: 727216

Gnomad4 AFR exome AF: 0.0650

Gnomad4 AMR exome AF: 0.0499

Gnomad4 ASJ exome AF: 0.0173

Gnomad4 EAS exome AF: 0.0352

Gnomad4 SAS exome AF: 0.0154

Gnomad4 FIN exome AF: 0.0563

Gnomad4 NFE exome AF: 0.00949

Gnomad4 OTH exome AF: 0.0209

GnomAD4 genome AF: 0.0327 AC: 4981 AN: 152248 Hom.: 118 Cov.: 32 AF XY: 0.0345 AC XY: 2565 AN XY: 74444

Gnomad4 AFR AF: 0.0630

Gnomad4 AMR AF: 0.0313

Gnomad4 ASJ AF: 0.0213

Gnomad4 EAS AF: 0.0485

Gnomad4 SAS AF: 0.0205

Gnomad4 FIN AF: 0.0573

Gnomad4 NFE AF: 0.0112

Gnomad4 OTH AF: 0.0379

Alfa AF: 0.0159 Hom.: 66

Bravo AF: 0.0338

TwinsUK AF: 0.0108 AC: 40

ALSPAC AF: 0.00623 AC: 24

ESP6500AA AF: 0.0672 AC: 296

ESP6500EA AF: 0.00953 AC: 82

ExAC AF: 0.0271 AC: 3289

Asia WGS AF: 0.0440 AC: 153 AN: 3478

EpiCase AF: 0.0114

EpiControl AF: 0.0106

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital plasminogen activator inhibitor type 1 deficiency 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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 09, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	0.0090
Dann	Benign	0.35
DEOGEN2	Benign	0.15	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.53	T
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	-0.26	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.010	N
REVEL	Benign	0.14
Sift	Benign	0.64	T
Sift4G	Benign	0.55	T
Polyphen		0.0	B
Vest4		0.0060
MPC		0.18
ClinPred		0.00030	T
GERP RS		-6.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.019
gMVP		0.095

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: rs6090; hg19: chr7-100771723; COSMIC: COSV56170583;