NM_000128.4:c.127G>A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP2

The NM_000128.4(F11):c.127G>A(p.Ala43Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,858 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

F11
NM_000128.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1O:1

Conservation

PhyloP100: 1.98

Publications

3 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: Uncertain_significance. The variant received 1 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F11	NM_000128.4 link	c.127G>A	p.Ala43Thr	missense_variant	Exon 3 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.127G>A	p.Ala43Thr	missense_variant	Exon 3 of 15	1	NM_000128.4	ENSP00000384957.2		P03951-1
F11	ENST00000492972.6 link	c.127G>A	p.Ala43Thr	missense_variant	Exon 3 of 5	2		ENSP00000424479.1		D6RB32

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000358

AC:

AN:

251460

AF XY:

0.0000442

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00000684

AC:

AN:

1461858

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727230

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.000157

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111980

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 28, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: F11 c.127G>A (p.Ala43Thr) results in a non-conservative amino acid change located in the Apple domain (IPR000177) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251460 control chromosomes. c.127G>A has been reported in the literature as heterozygous or compound heterozygous genotype in individuals affected with Hereditary factor XI deficiency disease with no detailed clinical presentations or segregation data (Rugeri_2010, Dai_2011). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary factor XI deficiency disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 76% reduction of extracellular F11 secretion (Dai_2011). The following publications have been ascertained in the context of this evaluation (PMID: 21457405, 20398070). ClinVar contains an entry for this variant (Variation ID: 68174). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

not provided

Other:1

UniProtKB/Swiss-Prot

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.64

D;D;.

Eigen

Benign

-0.11

Eigen_PC

Benign

-0.30

FATHMM_MKL

Benign

0.21

LIST_S2

Uncertain

0.87

D;D;D

M_CAP

Uncertain

0.090

MetaRNN

Uncertain

0.44

T;T;T

MetaSVM

Uncertain

0.12

MutationAssessor

Uncertain

2.6

M;.;M

PhyloP100

2.0

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.4

N;N;N

REVEL

Uncertain

0.38

Sift

Uncertain

0.0070

D;T;D

Sift4G

Uncertain

0.0080

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.30

MutPred

0.72

Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);

MVP

0.99

MPC

0.17

ClinPred

0.17

GERP RS

3.5

Varity_R

0.38

gMVP

0.68

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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NM_000128.4:c.127G>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over