rs2227635

Variant names:

• chr7-101127177-C-T
• rs2227635
• NM_000602.5:c.-69C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000602.5(SERPINE1):​c.-69C>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 0.0079 in 152,312 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0079 (14 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SERPINE1 NM_000602.5 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.375
• Publications: 2 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 Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0079 (1203/152312) while in subpopulation AFR AF = 0.0281 (1167/41572). AF 95% confidence interval is 0.0267. There are 14 homozygotes in GnomAd4. There are 550 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 14 AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINE1	NM_000602.5	MANE Select	c.-69C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 9	NP_000593.1
	SERPINE1	NM_000602.5	MANE Select	c.-69C>T		5_prime_UTR	Exon 1 of 9	NP_000593.1
	SERPINE1	NM_001386460.1		c.-69C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 9	NP_001373389.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINE1	ENST00000223095.5	TSL:1 MANE Select	c.-69C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 9	ENSP00000223095.4
	SERPINE1	ENST00000223095.5	TSL:1 MANE Select	c.-69C>T		5_prime_UTR	Exon 1 of 9	ENSP00000223095.4

Frequencies

GnomAD3 genomes AF: 0.00789 AC: 1201 AN: 152194 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.0281

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00138

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: 0.0000735

Gnomad OTH AF: 0.00478

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 474 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 356

African (AFR) AF: 0.00 AC: 0 AN: 14

American (AMR) AF: 0.00 AC: 0 AN: 6

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4

East Asian (EAS) AF: 0.00 AC: 0 AN: 10

South Asian (SAS) AF: 0.00 AC: 0 AN: 8

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 372

Other (OTH) AF: 0.00 AC: 0 AN: 26

GnomAD4 genome AF: 0.00790 AC: 1203 AN: 152312 Hom.: 14 Cov.: 32 AF XY: 0.00738 AC XY: 550 AN XY: 74490

African (AFR) AF: 0.0281 AC: 1167 AN: 41572

American (AMR) AF: 0.00137 AC: 21 AN: 15284

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68024

Other (OTH) AF: 0.00473 AC: 10 AN: 2112

Alfa AF: 0.00428 Hom.: 2

Bravo AF: 0.00897

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	7.5
DANN	Benign	0.62
PhyloP100		-0.38
PromoterAI		-0.097	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: rs2227635; hg19: chr7-100770458;