rs1057335

Variant names:

• chr17-1754359-G-A
• rs1057335
• NM_000934.4:c.1301G>A

Variant summary

Our verdict is Benign. The variant received -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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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
• Publications: 44 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: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 256834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.36 is higher than 0.05.

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.1301G>A	p.Arg434Lys	missense	Exon 10 of 10	NP_000925.2	P08697-1
	SERPINF2	NM_001165920.1		c.1301G>A	p.Arg434Lys	missense	Exon 10 of 10	NP_001159392.1	P08697-1
	SERPINF2	NM_001165921.2		c.1109G>A	p.Arg370Lys	missense	Exon 9 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.1301G>A	p.Arg434Lys	missense	Exon 10 of 10	ENSP00000402286.2	P08697-1
	SERPINF2	ENST00000382061.5	TSL:1	c.1301G>A	p.Arg434Lys	missense	Exon 10 of 10	ENSP00000371493.4	P08697-1
	SERPINF2	ENST00000883620.1		c.1463G>A	p.Arg488Lys	missense	Exon 11 of 11	ENSP00000553679.1

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

GnomAD2 exomes AF: 0.217 AC: 54417 AN: 251348 AF XY: 0.223

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 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

African (AFR) AF: 0.210 AC: 7027 AN: 33480

American (AMR) AF: 0.259 AC: 11582 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.178 AC: 4640 AN: 26136

East Asian (EAS) AF: 0.151 AC: 6012 AN: 39700

South Asian (SAS) AF: 0.374 AC: 32283 AN: 86258

European-Finnish (FIN) AF: 0.183 AC: 9752 AN: 53370

Middle Eastern (MID) AF: 0.254 AC: 1465 AN: 5766

European-Non Finnish (NFE) AF: 0.188 AC: 208551 AN: 1111990

Other (OTH) AF: 0.206 AC: 12434 AN: 60396

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

African (AFR) AF: 0.204 AC: 8462 AN: 41532

American (AMR) AF: 0.231 AC: 3540 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.170 AC: 590 AN: 3466

East Asian (EAS) AF: 0.149 AC: 773 AN: 5174

South Asian (SAS) AF: 0.374 AC: 1805 AN: 4820

European-Finnish (FIN) AF: 0.184 AC: 1948 AN: 10608

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.184 AC: 12544 AN: 68020

Other (OTH) AF: 0.204 AC: 431 AN: 2112

Alfa AF: 0.188 Hom.: 8428

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.64	T
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.93	L
PhyloP100		-0.051
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.36	N
REVEL	Benign	0.17
Sift	Benign	0.48	T
Sift4G	Benign	0.77	T
Polyphen		0.0010	B
Vest4		0.013
MPC		0.46
ClinPred		0.00055	T
GERP RS		0.74
Varity_R		0.096
gMVP		0.55
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1057335; hg19: chr17-1657653; COSMIC: COSV60663892; COSMIC: COSV60663892;