17-1745341-C-A

Variant names:

• chr17-1745341-C-A
• rs185025710
• NM_000934.4:c.111C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000934.4(SERPINF2):​c.111C>A​(p.Ser37Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,612,526 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. S37S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 28)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: SERPINF2 NM_000934.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.06
• Publications: 1 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: Orphanet, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1669259).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINF2	NM_000934.4	MANE Select	c.111C>A	p.Ser37Arg	missense	Exon 4 of 10	NP_000925.2	P08697-1
	SERPINF2	NM_001165920.1		c.111C>A	p.Ser37Arg	missense	Exon 4 of 10	NP_001159392.1	P08697-1
	SERPINF2	NM_001165921.2		c.111C>A	p.Ser37Arg	missense	Exon 4 of 9	NP_001159393.1	P08697-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINF2	ENST00000453066.6	TSL:5 MANE Select	c.111C>A	p.Ser37Arg	missense	Exon 4 of 10	ENSP00000402286.2	P08697-1
	SERPINF2	ENST00000382061.5	TSL:1	c.111C>A	p.Ser37Arg	missense	Exon 4 of 10	ENSP00000371493.4	P08697-1
	SERPINF2	ENST00000883620.1		c.111C>A	p.Ser37Arg	missense	Exon 4 of 11	ENSP00000553679.1

Frequencies

GnomAD3 genomes AF: 0.0000198 AC: 3 AN: 151508 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000295

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250546 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461018 Hom.: 0 Cov.: 43 AF XY: 0.00000550 AC XY: 4 AN XY: 726802

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52838

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5728

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111846

Other (OTH) AF: 0.0000166 AC: 1 AN: 60354

GnomAD4 genome AF: 0.0000198 AC: 3 AN: 151508 Hom.: 0 Cov.: 28 AF XY: 0.0000135 AC XY: 1 AN XY: 73968

African (AFR) AF: 0.0000242 AC: 1 AN: 41250

American (AMR) AF: 0.00 AC: 0 AN: 15182

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5132

South Asian (SAS) AF: 0.00 AC: 0 AN: 4786

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10522

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000295 AC: 2 AN: 67868

Other (OTH) AF: 0.00 AC: 0 AN: 2080

Alfa AF: 0.0000164 Hom.: 1

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.022	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	0.015
DANN	Benign	0.78
DEOGEN2	Benign	0.20	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.48	T
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.39	T
MutationAssessor	Benign	1.5	L
PhyloP100		-1.1
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.84	N
REVEL	Uncertain	0.41
Sift	Benign	0.058	T
Sift4G	Uncertain	0.043	D
Polyphen		0.61	P
Vest4		0.10
MutPred		0.25		Gain of solvent accessibility (P = 0.006)
MVP		0.49
MPC		0.52
ClinPred		0.10	T
GERP RS		-8.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.084
gMVP		0.34
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

dbSNP: rs185025710; hg19: chr17-1648635;