Genetic Variant SERPINE3:p.Thr319Ile (chr13-51355099-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001386375.1(SERPINE3):c.956C>T(p.Thr319Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000714 in 1,399,974 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T319S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

SERPINE3
NM_001386375.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.08

Publications

0 publications found

Variant links:

Genes affected

SERPINE3 (HGNC:24774): (serpin family E member 3) Predicted to enable serine-type endopeptidase inhibitor activity. Predicted to be involved in negative regulation of endopeptidase activity. Predicted to be active in extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

SERPINE3 links:

INTS6 (HGNC:14879): (integrator complex subunit 6) DEAD box proteins, characterized by the conserved motif Asp-Glu-Ala-Asp (DEAD), are putative RNA helicases. The protein encoded by this gene is a DEAD box protein that is part of a complex that interacts with the C-terminus of RNA polymerase II and is involved in 3' end processing of snRNAs. In addition, this gene is a candidate tumor suppressor and is located in the critical region of loss of heterozygosity (LOH). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2015]

INTS6 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.18206659).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINE3	NM_001386375.1 link	c.956C>T	p.Thr319Ile	missense_variant	Exon 7 of 10	ENST00000681248.1	NP_001373304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINE3	ENST00000681248.1 link	c.956C>T	p.Thr319Ile	missense_variant	Exon 7 of 10		NM_001386375.1	ENSP00000506411.1		A8MV23-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.14e-7

AC:

AN:

1399974

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

691146

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

31916

American (AMR)

AF:

0.00

AC:

AN:

36196

Ashkenazi Jewish (ASJ)

AF:

0.0000395

AC:

AN:

25294

East Asian (EAS)

AF:

0.00

AC:

AN:

36460

South Asian (SAS)

AF:

0.00

AC:

AN:

79378

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49542

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5696

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1077426

Other (OTH)

AF:

0.00

AC:

AN:

58066

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.080

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.29

.;T;.

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.40

FATHMM_MKL

Benign

0.41

LIST_S2

Benign

0.61

.;T;T

M_CAP

Benign

0.078

MetaRNN

Benign

0.18

T;T;T

MetaSVM

Benign

-0.45

MutationAssessor

Benign

2.0

M;M;M

PhyloP100

1.1

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-4.1

D;D;D

REVEL

Benign

0.23

Sift

Benign

0.096

T;T;T

Sift4G

Benign

0.089

T;T;T

Polyphen

0.028

B;B;B

Vest4

0.10

MutPred

0.54

Gain of catalytic residue at D320 (P = 0.0028);Gain of catalytic residue at D320 (P = 0.0028);Gain of catalytic residue at D320 (P = 0.0028);

MVP

0.78

MPC

0.32

ClinPred

0.86

GERP RS

0.94

Varity_R

0.24

gMVP

0.65

Mutation Taster

=79/21

polymorphism

(source)

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

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13-51355099-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over