17-1754289-G-A

Variant names:

• chr17-1754289-G-A
• rs121965062
• NM_000934.4:c.1231G>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

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
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: -0.196
• Publications: 5 publications found

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

ACMG classification

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINF2	NM_000934.4	c.1231G>A	p.Val411Met	missense_variant	Exon 10 of 10	ENST00000453066.6	NP_000925.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINF2	ENST00000453066.6	c.1231G>A	p.Val411Met	missense_variant	Exon 10 of 10	5	NM_000934.4	ENSP00000402286.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Alpha-2-plasmin inhibitor deficiency Pathogenic:1

Nov 01, 1999

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.028	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D;.;D
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.85	D;D;.
M_CAP	Benign	0.010	T
MetaRNN	Pathogenic	0.86	D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L;.;L
PhyloP100		-0.20
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.3	N;N;N
REVEL	Benign	0.25
Sift	Uncertain	0.0060	D;D;D
Sift4G	Benign	0.10	T;T;T
Polyphen		0.99	D;.;D
Vest4		0.14
MutPred		0.90		Gain of disorder (P = 0.0483);.;Gain of disorder (P = 0.0483);
MVP		0.53
MPC		0.89
ClinPred		0.42	T
GERP RS		0.31
Varity_R		0.28
gMVP		0.72
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121965062; hg19: chr17-1657583; COSMIC: COSV100131978; COSMIC: COSV100131978;