Genetic Variant NM_000934.4:c.1301G>A (chr17-1754359-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000934.4(SERPINF2):c.1301G>A(p.Arg434Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.201 in 1,614,050 control chromosomes in the GnomAD database, including 34,592 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.20 ( 3125 hom., cov: 33)

Exomes 𝑓: 0.20 ( 31467 hom. )

Consequence

SERPINF2
NM_000934.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.0510

Variant links:

Genes affected

SERPINF2 (HGNC:9075): (serpin family F member 2) This gene encodes a member of the serpin family of serine protease inhibitors. The protein is a major inhibitor of plasmin, which degrades fibrin and various other proteins. Consequently, the proper function of this gene has a major role in regulating the blood clotting pathway. Mutations in this gene result in alpha-2-plasmin inhibitor deficiency, which is characterized by severe hemorrhagic diathesis. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2009]

SERPINF2 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0024048686).

BP6

Variant 17-1754359-G-A is Benign according to our data. Variant chr17-1754359-G-A is described in ClinVar as [Benign]. Clinvar id is 256834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-1754359-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.36 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINF2	NM_000934.4 link	c.1301G>A	p.Arg434Lys	missense_variant	Exon 10 of 10	ENST00000453066.6	NP_000925.2	P08697-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINF2	ENST00000453066.6 link	c.1301G>A	p.Arg434Lys	missense_variant	Exon 10 of 10	5	NM_000934.4	ENSP00000402286.2		P08697-1C9JMH6

Frequencies

GnomAD3 genomes

AF:

0.199

AC:

30328

AN:

152112

Hom.:

3121

Cov.:

show subpopulations

Gnomad AFR

AF:

0.204

Gnomad AMI

AF:

0.241

Gnomad AMR

AF:

0.231

Gnomad ASJ

AF:

0.170

Gnomad EAS

AF:

0.149

Gnomad SAS

AF:

0.375

Gnomad FIN

AF:

0.184

Gnomad MID

AF:

0.165

Gnomad NFE

AF:

0.184

Gnomad OTH

AF:

0.199

GnomAD3 exomes

AF:

0.217

AC:

54417

AN:

251348

Hom.:

6534

AF XY:

0.223

AC XY:

30249

AN XY:

135856

show subpopulations

Gnomad AFR exome

AF:

0.210

Gnomad AMR exome

AF:

0.265

Gnomad ASJ exome

AF:

0.172

Gnomad EAS exome

AF:

0.143

Gnomad SAS exome

AF:

0.375

Gnomad FIN exome

AF:

0.184

Gnomad NFE exome

AF:

0.183

Gnomad OTH exome

AF:

0.200

GnomAD4 exome

AF:

0.201

AC:

293746

AN:

1461820

Hom.:

31467

Cov.:

AF XY:

0.206

AC XY:

149750

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.210

Gnomad4 AMR exome

AF:

0.259

Gnomad4 ASJ exome

AF:

0.178

Gnomad4 EAS exome

AF:

0.151

Gnomad4 SAS exome

AF:

0.374

Gnomad4 FIN exome

AF:

0.183

Gnomad4 NFE exome

AF:

0.188

Gnomad4 OTH exome

AF:

0.206

GnomAD4 genome

AF:

0.199

AC:

30359

AN:

152230

Hom.:

3125

Cov.:

AF XY:

0.205

AC XY:

15257

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.204

Gnomad4 AMR

AF:

0.231

Gnomad4 ASJ

AF:

0.170

Gnomad4 EAS

AF:

0.149

Gnomad4 SAS

AF:

0.374

Gnomad4 FIN

AF:

0.184

Gnomad4 NFE

AF:

0.184

Gnomad4 OTH

AF:

0.204

Alfa

AF:

0.186

Hom.:

5305

Bravo

AF:

0.197

TwinsUK

AF:

0.187

AC:

695

ALSPAC

AF:

0.181

AC:

697

ESP6500AA

AF:

0.212

AC:

932

ESP6500EA

AF:

0.180

AC:

1547

ExAC

AF:

0.216

AC:

26270

Asia WGS

AF:

0.309

AC:

1072

AN:

3478

EpiCase

AF:

0.185

EpiControl

AF:

0.179

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Benign

0.81

DEOGEN2

Benign

0.21

T;.;T

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.68

FATHMM_MKL

Benign

0.58

LIST_S2

Benign

0.64

T;T;.

MetaRNN

Benign

0.0024

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.93

L;.;L

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.36

N;N;N

REVEL

Benign

0.17

Sift

Benign

0.48

T;T;T

Sift4G

Benign

0.77

T;T;T

Polyphen

0.0010

B;.;B

Vest4

0.013

MPC

0.46

ClinPred

0.00055

GERP RS

0.74

Varity_R

0.096

gMVP

0.55

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over