rs1057335

Positions:

• chr17-1754359-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000934.4(SERPINF2):​c.1301G>A​(p.Arg434Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.201 in 1,614,050 control chromosomes in the GnomAD database, including 34,592 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.20 (3125 hom., cov: 33)
  • Exomes 𝑓: 0.20 (31467 hom.)
• Consequence: SERPINF2 NM_000934.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0510

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0024048686).
• BP6: Variant 17-1754359-G-A is Benign according to our data. Variant chr17-1754359-G-A is described in ClinVar as [Benign]. Clinvar id is 256834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-1754359-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.36 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SERPINF2	NM_000934.4	c.1301G>A	p.Arg434Lys	missense_variant	10/10	ENST00000453066.6	NP_000925.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SERPINF2	ENST00000453066.6	c.1301G>A	p.Arg434Lys	missense_variant	10/10	5	NM_000934.4	ENSP00000402286.2
SERPINF2	ENST00000382061.5	c.1301G>A	p.Arg434Lys	missense_variant	10/10	1		ENSP00000371493.4
SERPINF2	ENST00000324015.7	c.1301G>A	p.Arg434Lys	missense_variant	10/10	5		ENSP00000321853.3
SERPINF2	ENST00000450523.6	c.1109G>A	p.Arg370Lys	missense_variant	9/9	2		ENSP00000403877.2

Frequencies

GnomAD3 genomes AF: 0.199 AC: 30328 AN: 152112 Hom.: 3121 Cov.: 33

Gnomad AFR AF: 0.204

Gnomad AMI AF: 0.241

Gnomad AMR AF: 0.231

Gnomad ASJ AF: 0.170

Gnomad EAS AF: 0.149

Gnomad SAS AF: 0.375

Gnomad FIN AF: 0.184

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.184

Gnomad OTH AF: 0.199

GnomAD3 exomes AF: 0.217 AC: 54417 AN: 251348 Hom.: 6534 AF XY: 0.223 AC XY: 30249 AN XY: 135856

Gnomad AFR exome AF: 0.210

Gnomad AMR exome AF: 0.265

Gnomad ASJ exome AF: 0.172

Gnomad EAS exome AF: 0.143

Gnomad SAS exome AF: 0.375

Gnomad FIN exome AF: 0.184

Gnomad NFE exome AF: 0.183

Gnomad OTH exome AF: 0.200

GnomAD4 exome AF: 0.201 AC: 293746 AN: 1461820 Hom.: 31467 Cov.: 40 AF XY: 0.206 AC XY: 149750 AN XY: 727206

Gnomad4 AFR exome AF: 0.210

Gnomad4 AMR exome AF: 0.259

Gnomad4 ASJ exome AF: 0.178

Gnomad4 EAS exome AF: 0.151

Gnomad4 SAS exome AF: 0.374

Gnomad4 FIN exome AF: 0.183

Gnomad4 NFE exome AF: 0.188

Gnomad4 OTH exome AF: 0.206

GnomAD4 genome AF: 0.199 AC: 30359 AN: 152230 Hom.: 3125 Cov.: 33 AF XY: 0.205 AC XY: 15257 AN XY: 74418

Gnomad4 AFR AF: 0.204

Gnomad4 AMR AF: 0.231

Gnomad4 ASJ AF: 0.170

Gnomad4 EAS AF: 0.149

Gnomad4 SAS AF: 0.374

Gnomad4 FIN AF: 0.184

Gnomad4 NFE AF: 0.184

Gnomad4 OTH AF: 0.204

Alfa AF: 0.186 Hom.: 5305

Bravo AF: 0.197

TwinsUK AF: 0.187 AC: 695

ALSPAC AF: 0.181 AC: 697

ESP6500AA AF: 0.212 AC: 932

ESP6500EA AF: 0.180 AC: 1547

ExAC AF: 0.216 AC: 26270

Asia WGS AF: 0.309 AC: 1072 AN: 3478

EpiCase AF: 0.185

EpiControl AF: 0.179

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	13
DANN	Benign	0.81
DEOGEN2	Benign	0.21	T;.;T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.64	T;T;.
MetaRNN	Benign	0.0024	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.93	L;.;L
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.36	N;N;N
REVEL	Benign	0.17
Sift	Benign	0.48	T;T;T
Sift4G	Benign	0.77	T;T;T
Polyphen		0.0010	B;.;B
Vest4		0.013
MPC		0.46
ClinPred		0.00055	T
GERP RS		0.74
Varity_R		0.096
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1057335; hg19: chr17-1657653; COSMIC: COSV60663892; COSMIC: COSV60663892;