chr7-101128467-A-C

Variant names:

• chr7-101128467-A-C
• rs2227647
• NM_000602.5:c.74A>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_000602.5(SERPINE1):​c.74A>C​(p.His25Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000545 in 1,614,120 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: SERPINE1 NM_000602.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0850
• Publications: 6 publications found

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: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.016480327).
• BP6: Variant 7-101128467-A-C is Benign according to our data. Variant chr7-101128467-A-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1123294.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000602.5. 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
	SERPINE1	NM_000602.5	MANE Select	c.74A>C	p.His25Pro	missense	Exon 2 of 9	NP_000593.1	P05121-1
	SERPINE1	NM_001386460.1		c.74A>C	p.His25Pro	missense	Exon 2 of 9	NP_001373389.1
	SERPINE1	NM_001386461.1		c.74A>C	p.His25Pro	missense	Exon 2 of 8	NP_001373390.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINE1	ENST00000223095.5	TSL:1 MANE Select	c.74A>C	p.His25Pro	missense	Exon 2 of 9	ENSP00000223095.4	P05121-1
	SERPINE1	ENST00000950060.1		c.74A>C	p.His25Pro	missense	Exon 2 of 9	ENSP00000620119.1
	SERPINE1	ENST00000950062.1		c.74A>C	p.His25Pro	missense	Exon 2 of 9	ENSP00000620121.1

Frequencies

GnomAD3 genomes AF: 0.000296 AC: 45 AN: 152118 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00106

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000756 AC: 19 AN: 251308 AF XY: 0.0000810

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000294 AC: 43 AN: 1461884 Hom.: 0 Cov.: 33 AF XY: 0.0000289 AC XY: 21 AN XY: 727242

African (AFR) AF: 0.00108 AC: 36 AN: 33480

American (AMR) AF: 0.0000671 AC: 3 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112006

Other (OTH) AF: 0.0000662 AC: 4 AN: 60396

GnomAD4 genome AF: 0.000296 AC: 45 AN: 152236 Hom.: 0 Cov.: 32 AF XY: 0.000390 AC XY: 29 AN XY: 74418

African (AFR) AF: 0.00106 AC: 44 AN: 41540

American (AMR) AF: 0.0000654 AC: 1 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68000

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000155 Hom.: 0

Bravo AF: 0.000351

ExAC AF: 0.0000824 AC: 10

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	1.1
DANN	Benign	0.33
DEOGEN2	Benign	0.13	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.26	T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.016	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.34	N
PhyloP100		-0.085
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.70	N
REVEL	Benign	0.18
Sift	Benign	0.23	T
Sift4G	Benign	0.31	T
Polyphen		0.0	B
Vest4		0.10
MVP		0.72
MPC		0.35
ClinPred		0.0038	T
GERP RS		-2.2
Varity_R		0.29
gMVP		0.31
Mutation Taster		=95/5	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: rs2227647; hg19: chr7-100771748;