4-186288548-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_000128.4(F11):c.1812G>T(p.Arg604Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0529 in 1,613,998 control chromosomes in the GnomAD database, including 2,779 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. R604R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.069 ( 465 hom., cov: 32)

Exomes 𝑓: 0.051 ( 2314 hom. )

Consequence

F11
NM_000128.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -1.77

Publications

10 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 links:

F11-AS1 (HGNC:27725): (F11 antisense RNA 1)

F11-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (REVEL=0.046).

BP6

Variant 4-186288548-G-T is Benign according to our data. Variant chr4-186288548-G-T is described in ClinVar as Benign. ClinVar VariationId is 255178.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.77 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.113 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F11	NM_000128.4 link	c.1812G>T	p.Arg604Arg	synonymous_variant	Exon 15 of 15	ENST00000403665.7	NP_000119.1	P03951-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
F11	ENST00000403665.7 link	c.1812G>T	p.Arg604Arg	synonymous_variant	Exon 15 of 15	1	NM_000128.4	ENSP00000384957.2	P03951-1
F11-AS1	ENST00000505103.5 link	n.885C>A		non_coding_transcript_exon_variant	Exon 3 of 4	1
F11	ENST00000264691.4 link	c.411G>T	p.Arg137Arg	synonymous_variant	Exon 3 of 3	3		ENSP00000264691.4	X6R3B1
F11	ENST00000503841.1 link	n.331G>T		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes

AF:

0.0689

AC:

10483

AN:

152072

Hom.:

458

Cov.:

show subpopulations

Gnomad AFR

AF:

0.116

Gnomad AMI

AF:

0.0793

Gnomad AMR

AF:

0.0599

Gnomad ASJ

AF:

0.0816

Gnomad EAS

AF:

0.0678

Gnomad SAS

AF:

0.0791

Gnomad FIN

AF:

0.0382

Gnomad MID

AF:

0.108

Gnomad NFE

AF:

0.0460

Gnomad OTH

AF:

0.0551

GnomAD2 exomes

AF:

0.0609

AC:

15323

AN:

251480

AF XY:

0.0604

show subpopulations

Gnomad AFR exome

AF:

0.118

Gnomad AMR exome

AF:

0.0708

Gnomad ASJ exome

AF:

0.0814

Gnomad EAS exome

AF:

0.0704

Gnomad FIN exome

AF:

0.0389

Gnomad NFE exome

AF:

0.0464

Gnomad OTH exome

AF:

0.0594

GnomAD4 exome

AF:

0.0513

AC:

74938

AN:

1461808

Hom.:

2314

Cov.:

AF XY:

0.0520

AC XY:

37841

AN XY:

727214

show subpopulations

African (AFR)

AF:

0.126

AC:

4202

AN:

33468

American (AMR)

AF:

0.0701

AC:

3136

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0822

AC:

2149

AN:

26132

East Asian (EAS)

AF:

0.0813

AC:

3227

AN:

39700

South Asian (SAS)

AF:

0.0775

AC:

6689

AN:

86256

European-Finnish (FIN)

AF:

0.0383

AC:

2047

AN:

53414

Middle Eastern (MID)

AF:

0.120

AC:

695

AN:

5768

European-Non Finnish (NFE)

AF:

0.0444

AC:

49350

AN:

1111952

Other (OTH)

AF:

0.0570

AC:

3443

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.451

Heterozygous variant carriers

4232

8464

12696

16928

21160

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1958

3916

5874

7832

9790

<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:

0.0691

AC:

10515

AN:

152190

Hom.:

465

Cov.:

AF XY:

0.0693

AC XY:

5154

AN XY:

74406

show subpopulations

African (AFR)

AF:

0.116

AC:

4825

AN:

41534

American (AMR)

AF:

0.0604

AC:

923

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0816

AC:

283

AN:

3470

East Asian (EAS)

AF:

0.0677

AC:

350

AN:

5168

South Asian (SAS)

AF:

0.0794

AC:

382

AN:

4814

European-Finnish (FIN)

AF:

0.0382

AC:

405

AN:

10602

Middle Eastern (MID)

AF:

0.103

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0460

AC:

3131

AN:

68010

Other (OTH)

AF:

0.0541

AC:

114

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

477

955

1432

1910

2387

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

122

244

366

488

610

<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:

0.0565

Hom.:

582

Bravo

AF:

0.0730

Asia WGS

AF:

0.0530

AC:

185

AN:

3478

EpiCase

AF:

0.0516

EpiControl

AF:

0.0506

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

May 04, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

- -

Hereditary factor XI deficiency disease

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jul 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Plasma factor XI deficiency

Benign:1

Nov 21, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.61

CADD

Benign

(source)

DANN

Benign

0.82

PhyloP100

-1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Mutation Taster

=100/0

polymorphism (auto)

(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