rs121965070

Variant names:

• chr4-186280065-A-T
• rs121965070
• NM_000128.4:c.809A>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PS3 PP2 PP5

The NM_000128.4(F11):​c.809A>T​(p.Lys270Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000544 in 1,614,012 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV000448987: Functional studies in hamster kidney cells demonstrated that while the p.Lys270Ile variant protein was synthesized and expressed intracellularly at levels similar to wild type, secretion of the variant protein was reduced by 73% (Dai et al. 2004)." and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00052 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00055 (0 hom.)
• Consequence: F11 NM_000128.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:3 O:1
• Conservation: PhyloP100: -0.442
• Publications: 5 publications found

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: AR, AD, SD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000448987: Functional studies in hamster kidney cells demonstrated that while the p.Lys270Ile variant protein was synthesized and expressed intracellularly at levels similar to wild type, secretion of the variant protein was reduced by 73% (Dai et al. 2004).; SCV005397319: An in vitro functiol study demonstrated that cells expressing variant factor XI had ~66% decreased secretion in comparison to cells expressing wild-type protein (PMID: 15180874).
• 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.
• PP5: Variant 4-186280065-A-T is Pathogenic according to our data. Variant chr4-186280065-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 11902.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000128.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F11	NM_000128.4	MANE Select	c.809A>T	p.Lys270Ile	missense	Exon 8 of 15	NP_000119.1	P03951-1
	F11	NM_001440590.1		c.809A>T	p.Lys270Ile	missense	Exon 8 of 15	NP_001427519.1
	F11	NM_001440593.1		c.809A>T	p.Lys270Ile	missense	Exon 8 of 14	NP_001427522.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F11	ENST00000403665.7	TSL:1 MANE Select	c.809A>T	p.Lys270Ile	missense	Exon 8 of 15	ENSP00000384957.2	P03951-1
	F11	ENST00000886358.1		c.809A>T	p.Lys270Ile	missense	Exon 8 of 16	ENSP00000556417.1
	F11	ENST00000886339.1		c.809A>T	p.Lys270Ile	missense	Exon 8 of 15	ENSP00000556398.1

Frequencies

GnomAD3 genomes AF: 0.000519 AC: 79 AN: 152172 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000794

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000497 AC: 125 AN: 251364 AF XY: 0.000478

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00120

Gnomad NFE exome AF: 0.000818

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000547 AC: 799 AN: 1461840 Hom.: 0 Cov.: 33 AF XY: 0.000529 AC XY: 385 AN XY: 727216

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.0000671 AC: 3 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86254

European-Finnish (FIN) AF: 0.00133 AC: 71 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000633 AC: 704 AN: 1111964

Other (OTH) AF: 0.000281 AC: 17 AN: 60396

GnomAD4 genome AF: 0.000519 AC: 79 AN: 152172 Hom.: 0 Cov.: 32 AF XY: 0.000538 AC XY: 40 AN XY: 74324

African (AFR) AF: 0.000193 AC: 8 AN: 41432

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00151 AC: 16 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000794 AC: 54 AN: 68034

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.000864 Hom.: 0

Bravo AF: 0.000427

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.000445 AC: 54

EpiCase AF: 0.000491

EpiControl AF: 0.000889

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
3	2	-	Hereditary factor XI deficiency disease (5)
-	1	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	12
DANN	Benign	0.86
DEOGEN2	Uncertain	0.47	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.047	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.60	N
PhyloP100		-0.44
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.54
Sift	Benign	0.15	T
Sift4G	Benign	0.15	T
Polyphen		0.0060	B
Vest4		0.57
MVP		0.77
MPC		0.20
ClinPred		0.0081	T
GERP RS		-7.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.25
gMVP		0.71
Mutation Taster		=22/78	disease causing (ClinVar)

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: rs121965070; hg19: chr4-187201219;