17-1745766-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000934.4(SERPINF2):c.224C>A(p.Thr75Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,738 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SERPINF2 NM_000934.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.981

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16848978).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPINF2	NM_000934.4	c.224C>A	p.Thr75Asn	missense_variant	5/10	ENST00000453066.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINF2	ENST00000453066.6	c.224C>A	p.Thr75Asn	missense_variant	5/10	5	NM_000934.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461738 Hom.: 0 Cov.: 34 AF XY: 0.00000413 AC XY: 3 AN XY: 727166

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 15, 2023

The c.224C>A (p.T75N) alteration is located in exon 5 (coding exon 4) of the SERPINF2 gene. This alteration results from a C to A substitution at nucleotide position 224, causing the threonine (T) at amino acid position 75 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	13
Dann	Benign	0.89
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.58	T;T;T;.
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.17	T;T;T;T
MetaSVM	Uncertain	-0.16	T
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.7	N;N;N;N
REVEL	Benign	0.070
Sift	Benign	0.087	T;T;T;T
Sift4G	Uncertain	0.013	D;D;T;D
Polyphen		0.0010	.;B;.;B
Vest4		0.14, 0.14
MutPred		0.37		Loss of phosphorylation at T75 (P = 0.0023);Loss of phosphorylation at T75 (P = 0.0023);Loss of phosphorylation at T75 (P = 0.0023);Loss of phosphorylation at T75 (P = 0.0023);
MVP		0.82
MPC		0.52
ClinPred		0.13	T
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.076
gMVP		0.23

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-1649060;