dbSNP rs121965062: SERPINF2:p.Val411Met (chr17-1754289-G-A) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The NM_000934.4(SERPINF2):c.1231G>A(p.Val411Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 33)

Consequence

SERPINF2
NM_000934.4 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: -0.196

Publications

5 publications found

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 Gene-Disease associations (from GenCC):

alpha-2-plasmin inhibitor deficiency
Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia

SERPINF2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.864

PP5

Variant 17-1754289-G-A is Pathogenic according to our data. Variant chr17-1754289-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 276.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000934.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SERPINF2	NM_000934.4	MANE Select	c.1231G>A	p.Val411Met	missense	Exon 10 of 10	NP_000925.2	P08697-1
SERPINF2	NM_001165920.1		c.1231G>A	p.Val411Met	missense	Exon 10 of 10	NP_001159392.1	P08697-1
SERPINF2	NM_001165921.2		c.1039G>A	p.Val347Met	missense	Exon 9 of 9	NP_001159393.1	P08697-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SERPINF2	ENST00000453066.6	TSL:5 MANE Select	c.1231G>A	p.Val411Met	missense	Exon 10 of 10	ENSP00000402286.2	P08697-1
SERPINF2	ENST00000382061.5	TSL:1	c.1231G>A	p.Val411Met	missense	Exon 10 of 10	ENSP00000371493.4	P08697-1
SERPINF2	ENST00000883620.1		c.1393G>A	p.Val465Met	missense	Exon 11 of 11	ENSP00000553679.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Alpha-2-plasmin inhibitor deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.028

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.58

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.33

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.85

M_CAP

Benign

0.010

MetaRNN

Pathogenic

0.86

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

PhyloP100

-0.20

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.3

REVEL

Benign

0.25

Sift

Uncertain

0.0060

Sift4G

Benign

0.10

Polyphen

0.99

Vest4

0.14

MutPred

0.90

Gain of disorder (P = 0.0483)

MVP

0.53

MPC

0.89

ClinPred

0.42

GERP RS

0.31

Varity_R

0.28

gMVP

0.72

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over