rs1459304265

Positions:

• chr4-186276275-AACATCG-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PM4 PP5_Very_Strong

The NM_000128.4(F11):​c.644_649delTCGACA​(p.Ile215_Asp216del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: F11 NM_000128.4 disruptive_inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 2.85

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 Pathogenic. Variant got 14 ACMG points.

• PM1: In a domain Apple 3 (size 83) in uniprot entity FA11_HUMAN there are 20 pathogenic changes around while only 0 benign (100%) in NM_000128.4
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000128.4.
• PP5: Variant 4-186276275-AACATCG-A is Pathogenic according to our data. Variant chr4-186276275-AACATCG-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 558063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
F11	NM_000128.4	c.644_649delTCGACA	p.Ile215_Asp216del	disruptive_inframe_deletion	7/15	ENST00000403665.7	NP_000119.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F11	ENST00000403665.7	c.644_649delTCGACA	p.Ile215_Asp216del	disruptive_inframe_deletion	7/15	1	NM_000128.4	ENSP00000384957.2
F11	ENST00000452239.1	c.89_94delTCGACA	p.Ile30_Asp31del	disruptive_inframe_deletion	2/6	5		ENSP00000397401.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461892 Hom.: 0 AF XY: 0.00000275 AC XY: 2 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.000447 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary factor XI deficiency disease Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 16, 2023	Variant summary: F11 c.644_649delTCGACA (p.Ile215_Asp216del) results in an in-frame deletion that is predicted to remove two amino acids from the encoded protein. The variant was absent in 251372 control chromosomes (gnomAD v2 Exomes dataset). c.644_649delTCGACA has been reported in the literature in at least one compound heterozygous as well as several heterozygous individuals affected with Hereditary factor XI deficiency disease (e.g., Zadra_2004, Dossenbach-Glaninger_2006, Fard-Esfahani_2007, Bicocchi_2013, Najm_2018). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant results in <1% FXI coagulant activity and 17% FXI antigen levels relative to wild-type in conditioned media in vitro, which is likely due to impaired folding and secretion (e.g., Zadra_2004). Additionally, co-transfection with the wild-type and variant proteins only partially rescued secreted antigen levels to approximately 63% suggesting a potential dominant-negative impact of the variant (Zadra_2004). The following publications have been ascertained in the context of this evaluation (PMID: 23305485, 16519703, 18005151, 30261521, 15531455). One submitter has reported clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Apr 26, 2018	- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1459304265; hg19: chr4-187197429;