rs5967

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_000128.4(F11):c.1016G>T(p.Cys339Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0011 in 1,614,182 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0055 ( 7 hom., cov: 32)

Exomes 𝑓: 0.00064 ( 12 hom. )

Consequence

F11
NM_000128.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.59

Publications

6 publications found

Variant links:

Genes affected

F11 (HGNC:3529): (coagulation factor XI) This gene encodes coagulation factor XI of the blood coagulation cascade. This protein is present in plasma as a zymogen, which is a unique plasma coagulation enzyme because it exists as a homodimer consisting of two identical polypeptide chains linked by disulfide bonds. During activation of the plasma factor XI, an internal peptide bond is cleaved by factor XIIa (or XII) in each of the two chains, resulting in activated factor XIa, a serine protease composed of two heavy and two light chains held together by disulfide bonds. This activated plasma factor XI triggers the middle phase of the intrisic pathway of blood coagulation by activating factor IX. Defects in this factor lead to Rosenthal syndrome, a blood coagulation abnormality. [provided by RefSeq, Jul 2008]

F11 Gene-Disease associations (from GenCC):

congenital factor XI deficiency
Inheritance: AD, AR, SD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen

F11 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 47 curated pathogenic missense variants (we use a threshold of 10). The gene has 7 curated benign missense variants. Gene score misZ: 0.019886 (below the threshold of 3.09). Trascript score misZ: 0.83889 (below the threshold of 3.09). GenCC associations: The gene is linked to congenital factor XI deficiency.

BP4

Computational evidence support a benign effect (MetaRNN=0.007949859).

BP6

Variant 4-186280373-G-T is Benign according to our data. Variant chr4-186280373-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 348375.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00552 (840/152306) while in subpopulation AFR AF = 0.0188 (781/41560). AF 95% confidence interval is 0.0177. There are 7 homozygotes in GnomAd4. There are 373 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 AD,AR,SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F11	NM_000128.4 link	c.1016G>T	p.Cys339Phe	missense_variant	Exon 9 of 15	ENST00000403665.7	NP_000119.1	P03951-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F11	ENST00000403665.7 link	c.1016G>T	p.Cys339Phe	missense_variant	Exon 9 of 15	1	NM_000128.4	ENSP00000384957.2		P03951-1
F11	ENST00000452239.1 link	c.461G>T	p.Cys154Phe	missense_variant	Exon 4 of 6	5		ENSP00000397401.1		H0Y596

Frequencies

GnomAD3 genomes

AF:

0.00553

AC:

841

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0189

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00242

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000220

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00154

AC:

388

AN:

251452

AF XY:

0.00113

show subpopulations

Gnomad AFR exome

AF:

0.0205

Gnomad AMR exome

AF:

0.000983

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000114

Gnomad OTH exome

AF:

0.00130

GnomAD4 exome

AF:

0.000643

AC:

940

AN:

1461876

Hom.:

Cov.:

AF XY:

0.000543

AC XY:

395

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.0208

AC:

695

AN:

33480

American (AMR)

AF:

0.00145

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53404

Middle Eastern (MID)

AF:

0.00381

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000603

AC:

AN:

1112010

Other (OTH)

AF:

0.00147

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

128

193

257

321

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00552

AC:

840

AN:

152306

Hom.:

Cov.:

AF XY:

0.00501

AC XY:

373

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.0188

AC:

781

AN:

41560

American (AMR)

AF:

0.00242

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000220

AC:

AN:

68028

Other (OTH)

AF:

0.00284

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

131

175

219

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00223

Hom.:

Bravo

AF:

0.00646

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0170

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00183

AC:

222

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Apr 01, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Hereditary factor XI deficiency disease

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

F11-related disorder

Benign:1

Feb 18, 2020

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.23

CADD

Benign

(source)

DANN

Benign

0.87

DEOGEN2

Pathogenic

0.90

D;.

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.45

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.72

T;T

MetaRNN

Benign

0.0079

T;T

MetaSVM

Benign

-0.50

MutationAssessor

Uncertain

2.7

M;.

PhyloP100

1.6

PrimateAI

Benign

0.36

PROVEAN

Pathogenic

-5.3

D;.

REVEL

Benign

0.27

Sift

Pathogenic

0.0

D;.

Sift4G

Uncertain

0.0040

D;D

Polyphen

0.72

P;.

Vest4

0.62

MVP

0.93

MPC

0.38

ClinPred

0.11

GERP RS

1.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.57

gMVP

0.85

Mutation Taster

=82/18

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over