17-1745000-C-T

Variant names:

• chr17-1745000-C-T
• rs2070862
• NM_000934.4:c.5C>T

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

• 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
• Publications: 39 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: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINF2	NM_000934.4	MANE Select	c.5C>T	p.Ala2Val	missense	Exon 2 of 10	NP_000925.2
	SERPINF2	NM_001165920.1		c.5C>T	p.Ala2Val	missense	Exon 2 of 10	NP_001159392.1
	SERPINF2	NM_001165921.2		c.5C>T	p.Ala2Val	missense	Exon 2 of 9	NP_001159393.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINF2	ENST00000453066.6	TSL:5 MANE Select	c.5C>T	p.Ala2Val	missense	Exon 2 of 10	ENSP00000402286.2
	SERPINF2	ENST00000382061.5	TSL:1	c.5C>T	p.Ala2Val	missense	Exon 2 of 10	ENSP00000371493.4
	SERPINF2	ENST00000324015.7	TSL:5	c.5C>T	p.Ala2Val	missense	Exon 2 of 10	ENSP00000321853.3

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

GnomAD2 exomes AF: 0.202 AC: 50613 AN: 250204 AF XY: 0.197

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 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

African (AFR) AF: 0.233 AC: 7815 AN: 33474

American (AMR) AF: 0.217 AC: 9717 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.141 AC: 3675 AN: 26136

East Asian (EAS) AF: 0.170 AC: 6761 AN: 39698

South Asian (SAS) AF: 0.121 AC: 10449 AN: 86252

European-Finnish (FIN) AF: 0.204 AC: 10862 AN: 53194

Middle Eastern (MID) AF: 0.113 AC: 649 AN: 5726

European-Non Finnish (NFE) AF: 0.231 AC: 256398 AN: 1111788

Other (OTH) AF: 0.203 AC: 12259 AN: 60382

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

African (AFR) AF: 0.233 AC: 9631 AN: 41400

American (AMR) AF: 0.208 AC: 3165 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.132 AC: 458 AN: 3468

East Asian (EAS) AF: 0.170 AC: 874 AN: 5138

South Asian (SAS) AF: 0.118 AC: 569 AN: 4824

European-Finnish (FIN) AF: 0.194 AC: 2047 AN: 10542

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.227 AC: 15423 AN: 67944

Other (OTH) AF: 0.191 AC: 401 AN: 2100

Alfa AF: 0.220 Hom.: 15024

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

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.054	N
LIST_S2	Benign	0.50	T
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N
PhyloP100		-0.49
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.97	N
REVEL	Benign	0.27
Sift	Benign	0.30	T
Sift4G	Benign	0.30	T
Polyphen		0.0030	B
Vest4		0.050
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
Mutation Taster		=95/5	polymorphism (auto)

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