17-1745790-C-G

Position:

• chr17-1745790-C-G

Variant summary

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

The NM_000934.4(SERPINF2):​c.248C>G​(p.Ala83Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: SERPINF2 NM_000934.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.04

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPINF2	NM_000934.4	c.248C>G	p.Ala83Gly	missense_variant	5/10	ENST00000453066.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINF2	ENST00000453066.6	c.248C>G	p.Ala83Gly	missense_variant	5/10	5	NM_000934.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 31

Bravo AF: 0.0000151

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

Jan 23, 2023

The c.248C>G (p.A83G) alteration is located in exon 5 (coding exon 4) of the SERPINF2 gene. This alteration results from a C to G substitution at nucleotide position 248, causing the alanine (A) at amino acid position 83 to be replaced by a glycine (G). 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	0.10
BayesDel_addAF	Uncertain	0.038	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	.;T;.;T
Eigen	Benign	0.013
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.75	T;T;T;.
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.71	D;D;D;D
MetaSVM	Uncertain	0.20	D
MutationAssessor	Benign	1.9	.;L;.;L
MutationTaster	Benign	0.96	D;D;D
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.58	N;N;N;N
REVEL	Benign	0.16
Sift	Benign	0.15	T;T;T;T
Sift4G	Benign	0.15	T;T;T;T
Polyphen		0.25	.;B;.;B
Vest4		0.32, 0.32
MutPred		0.75		Loss of stability (P = 0.0942);Loss of stability (P = 0.0942);Loss of stability (P = 0.0942);Loss of stability (P = 0.0942);
MVP		0.91
MPC		0.51
ClinPred		0.28	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.15
gMVP		0.40

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

LitVar

Other links and lift over

dbSNP: rs1335232241; hg19: chr17-1649084;