Genetic Variant F11:c.-2+120G>A (chr4-186266415-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000128.4(F11):c.-2+120G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.338 in 152,060 control chromosomes in the GnomAD database, including 9,058 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.34 ( 9058 hom., cov: 33)

Failed GnomAD Quality Control

Consequence

F11
NM_000128.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.00400

Publications

12 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.385 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F11	NM_000128.4 link	c.-2+120G>A		intron_variant	Intron 1 of 14	ENST00000403665.7	NP_000119.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F11	ENST00000403665.7 link	c.-2+120G>A		intron_variant	Intron 1 of 14	1	NM_000128.4	ENSP00000384957.2
F11	ENST00000492972.6 link	c.-2+120G>A		intron_variant	Intron 1 of 4	2		ENSP00000424479.1

Frequencies

GnomAD3 genomes

AF:

0.338

AC:

51289

AN:

151942

Hom.:

9041

Cov.:

show subpopulations

Gnomad AFR

AF:

0.227

Gnomad AMI

AF:

0.486

Gnomad AMR

AF:

0.358

Gnomad ASJ

AF:

0.361

Gnomad EAS

AF:

0.331

Gnomad SAS

AF:

0.283

Gnomad FIN

AF:

0.413

Gnomad MID

AF:

0.304

Gnomad NFE

AF:

0.389

Gnomad OTH

AF:

0.363

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.338

AC:

51339

AN:

152060

Hom.:

9058

Cov.:

AF XY:

0.337

AC XY:

25050

AN XY:

74324

show subpopulations

African (AFR)

AF:

0.228

AC:

9448

AN:

41480

American (AMR)

AF:

0.358

AC:

5464

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.361

AC:

1254

AN:

3470

East Asian (EAS)

AF:

0.331

AC:

1709

AN:

5170

South Asian (SAS)

AF:

0.283

AC:

1364

AN:

4816

European-Finnish (FIN)

AF:

0.413

AC:

4367

AN:

10570

Middle Eastern (MID)

AF:

0.313

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.389

AC:

26422

AN:

67968

Other (OTH)

AF:

0.367

AC:

776

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1729

3458

5186

6915

8644

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

506

1012

1518

2024

2530

<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:

0.369

Hom.:

34022

Bravo

AF:

0.328

Asia WGS

AF:

0.330

AC:

1149

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

2.0

(source)

DANN

Benign

0.65

PhyloP100

-0.0040

PromoterAI

0.0034

Neutral

(source)

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over