4-186280065-A-T

Position:

• chr4-186280065-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP5

The ENST00000403665.7(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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00052 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00055 (0 hom.)
• Consequence: F11 ENST00000403665.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:3 O:1
• Conservation: PhyloP100: -0.442

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a strand (size 9) in uniprot entity FA11_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in ENST00000403665.7
• PM2: Very rare variant in population databases, with high coverage
• 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 id is 11902.We mark this variant Likely_pathogenic, oryginal submissions are: {not_provided=1, Uncertain_significance=3, Likely_pathogenic=2}. Variant chr4-186280065-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
F11	NM_000128.4	c.809A>T	p.Lys270Ile	missense_variant	8/15	ENST00000403665.7	NP_000119.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F11	ENST00000403665.7	c.809A>T	p.Lys270Ile	missense_variant	8/15	1	NM_000128.4	ENSP00000384957.2
F11	ENST00000452239.1	c.254A>T	p.Lys85Ile	missense_variant	3/6	5		ENSP00000397401.1

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

GnomAD3 exomes AF: 0.000497 AC: 125 AN: 251364 Hom.: 0 AF XY: 0.000478 AC XY: 65 AN XY: 135856

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 SAS exome AF: 0.0000327

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

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00133

Gnomad4 NFE exome AF: 0.000633

Gnomad4 OTH exome AF: 0.000281

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

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00151

Gnomad4 NFE AF: 0.000794

Gnomad4 OTH AF: 0.000478

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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:3 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary factor XI deficiency disease Pathogenic:3 Uncertain:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	Jul 23, 2022	This sequence variant is a single nucleotide substitution (A>T) at coding position 809 in the F11 gene which results in a lysine to isoleucine amino acid change at residue 270 in the F11-encoded factor XI protein. This is a previously reported variant (ClinVar) which has been observed in heterozygous and compound heterozygous state in individuals with coagulation disorders (PMID: 18839438, 16835901, 18446632, 31064749). This variant is present in 148/282756 alleles (0.05234%) in the gnomAD control population dataset. This variant occurs in the third of four apple domains in factor XI. Bioinformatic tools predict that this amino acid change is likely to be tolerated; furthermore, this amino acid residue is not well conserved in vertebrates. However, 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). Furthermore, multiple individuals that were heterozygous or compound heterozygous for this variant had factor XI antigen and activity levels consistent with a nearly complete loss of function (PMID: 18839438, 16835901). Based on the current data, we consider this variant to be likely pathogenic. ACMG Criteria: BP4, PM3, PS3, PS4 -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Oct 01, 2021	NM_000128.3(F11):c.809A>T(K270I) is a missense variant classified as a variant of uncertain significance in the context of factor XI deficiency. K270I has been observed in cases with relevant disease (PMID: 15180874, 18839438, 18446632, 31064749). Functional assessments of this variant are available in the literature (PMID: 15180874). K270I has been observed in population frequency databases (gnomAD: FIN 0.13%). In summary, there is insufficient evidence to classify NM_000128.3(F11):c.809A>T(K270I) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -
Uncertain significance, criteria provided, single submitter	research	NIHR Bioresource Rare Diseases, University of Cambridge	Feb 01, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The F11 c.809A>T (p.Lys270Ile) missense variant, also known as p.Lys252Ile, has been reported in three studies and is found in a compound heterozygous state in at least four individuals with factor XI deficiency, two of whom were related, and in a heterozygous state in two family members of one of the compound heterozygotes, though phenotype information is not provided (Dai et al. 2004; Mitchell et al. 2006; Castaman et al. 2008). Control data are unavailable for this variant, which is reported at a frequency of 0.00151 in the European (Finnish) population of the Exome Aggregation Consortium. 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). Based on the evidence, the p.Lys270Ile variant is classified as likely pathogenic for factor XI deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2004	- -

not provided Uncertain:1 Other:1

not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 08, 2017	- -

Computational scores

Source: dbNSFP v4.3

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;T
M_CAP	Benign	0.047	D
MetaRNN	Uncertain	0.68	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.60	N;.
MutationTaster	Benign	1.7e-12	A;A
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.3	N;.
REVEL	Uncertain	0.54
Sift	Benign	0.15	T;.
Sift4G	Benign	0.15	T;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

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

LitVar

Other links and lift over

dbSNP: rs121965070; hg19: chr4-187201219;