rs2070862

Positions:

• chr17-1745000-C-T

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.5C>T​(p.Ala2Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.218 in 1,613,214 control chromosomes in the GnomAD database, including 39,047 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 0.22 (3540 hom., cov: 30)
  • Exomes 𝑓: 0.22 (35507 hom.)
• Consequence: SERPINF2 NM_000934.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.488

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=0.001448214).
• BP6: Variant 17-1745000-C-T is Benign according to our data. Variant chr17-1745000-C-T is described in ClinVar as [Benign]. Clinvar id is 256836.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.229 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SERPINF2	NM_000934.4	c.5C>T	p.Ala2Val	missense_variant	2/10	ENST00000453066.6	NP_000925.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SERPINF2	ENST00000453066.6	c.5C>T	p.Ala2Val	missense_variant	2/10	5	NM_000934.4	ENSP00000402286	P1

Frequencies

GnomAD3 genomes AF: 0.215 AC: 32669 AN: 151740 Hom.: 3536 Cov.: 30

Gnomad AFR AF: 0.233

Gnomad AMI AF: 0.0998

Gnomad AMR AF: 0.208

Gnomad ASJ AF: 0.132

Gnomad EAS AF: 0.170

Gnomad SAS AF: 0.118

Gnomad FIN AF: 0.194

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.227

Gnomad OTH AF: 0.192

GnomAD3 exomes AF: 0.202 AC: 50613 AN: 250204 Hom.: 5338 AF XY: 0.197 AC XY: 26748 AN XY: 135536

Gnomad AFR exome AF: 0.234

Gnomad AMR exome AF: 0.217

Gnomad ASJ exome AF: 0.137

Gnomad EAS exome AF: 0.176

Gnomad SAS exome AF: 0.117

Gnomad FIN exome AF: 0.197

Gnomad NFE exome AF: 0.227

Gnomad OTH exome AF: 0.204

GnomAD4 exome AF: 0.218 AC: 318585 AN: 1461356 Hom.: 35507 Cov.: 45 AF XY: 0.215 AC XY: 156267 AN XY: 726966

Gnomad4 AFR exome AF: 0.233

Gnomad4 AMR exome AF: 0.217

Gnomad4 ASJ exome AF: 0.141

Gnomad4 EAS exome AF: 0.170

Gnomad4 SAS exome AF: 0.121

Gnomad4 FIN exome AF: 0.204

Gnomad4 NFE exome AF: 0.231

Gnomad4 OTH exome AF: 0.203

GnomAD4 genome AF: 0.215 AC: 32704 AN: 151858 Hom.: 3540 Cov.: 30 AF XY: 0.210 AC XY: 15563 AN XY: 74204

Gnomad4 AFR AF: 0.233

Gnomad4 AMR AF: 0.208

Gnomad4 ASJ AF: 0.132

Gnomad4 EAS AF: 0.170

Gnomad4 SAS AF: 0.118

Gnomad4 FIN AF: 0.194

Gnomad4 NFE AF: 0.227

Gnomad4 OTH AF: 0.191

Alfa AF: 0.217 Hom.: 7427

Bravo AF: 0.221

TwinsUK AF: 0.264 AC: 979

ALSPAC AF: 0.238 AC: 919

ESP6500AA AF: 0.242 AC: 1065

ESP6500EA AF: 0.221 AC: 1902

ExAC AF: 0.206 AC: 24982

Asia WGS AF: 0.158 AC: 553 AN: 3478

EpiCase AF: 0.210

EpiControl AF: 0.216

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	10
DANN	Benign	0.94
DEOGEN2	Benign	0.20	.;T;.;.;T
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.054	N
LIST_S2	Benign	0.50	T;T;T;T;.
MetaRNN	Benign	0.0014	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	.;N;N;.;N
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.97	N;N;N;N;N
REVEL	Benign	0.27
Sift	Benign	0.30	T;T;T;D;T
Sift4G	Benign	0.30	T;T;T;T;T
Polyphen		0.0030	.;B;.;.;B
Vest4		0.050, 0.11, 0.053
MPC		0.45
ClinPred		0.0091	T
GERP RS		-0.87
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.069
gMVP		0.20

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: rs2070862; hg19: chr17-1648294; COSMIC: COSV60664172;