4-186267129-ATTGTAGGATGATTTTC-A

Variant names:

• chr4-186267129-ATTGTAGGATGATTTTC-A
• NM_000128.4:c.-1-4_11delGTAGGATGATTTTCTT

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM4 PP5_Moderate

The NM_000128.4(F11):​c.-1-4_11delGTAGGATGATTTTCTT​(p.Met1_Leu4del) variant causes a start lost, conservative inframe deletion, splice region change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: F11 NM_000128.4 start_lost, conservative_inframe_deletion, splice_region
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.94
• Publications: 0 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: AD, AR, SD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_000128.4.
• PP5: Variant 4-186267129-ATTGTAGGATGATTTTC-A is Pathogenic according to our data. Variant chr4-186267129-ATTGTAGGATGATTTTC-A is described in ClinVar as [Pathogenic]. Clinvar id is 2715165.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F11	NM_000128.4	c.-1-4_11delGTAGGATGATTTTCTT	p.Met1_Leu4del	start_lost, conservative_inframe_deletion, splice_region_variant	Exon 2 of 15	ENST00000403665.7	NP_000119.1
F11	NM_000128.4	c.-1-4_11delGTAGGATGATTTTCTT		splice_acceptor_variant, 5_prime_UTR_truncation, exon_loss_variant, splice_region_variant, intron_variant	Exon 2 of 15	ENST00000403665.7	NP_000119.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F11	ENST00000403665.7	c.-1-4_11delGTAGGATGATTTTCTT	p.Met1_Leu4del	start_lost, conservative_inframe_deletion, splice_region_variant	Exon 2 of 15	1	NM_000128.4	ENSP00000384957.2
F11	ENST00000403665.7	c.-1-4_11delGTAGGATGATTTTCTT		splice_acceptor_variant, 5_prime_UTR_truncation, exon_loss_variant, splice_region_variant, intron_variant	Exon 2 of 15	1	NM_000128.4	ENSP00000384957.2
F11	ENST00000492972.6	c.-1-4_11delGTAGGATGATTTTCTT	p.Met1_Leu4del	start_lost, conservative_inframe_deletion, splice_region_variant	Exon 2 of 5	2		ENSP00000424479.1
F11	ENST00000492972.6	c.-1-4_11delGTAGGATGATTTTCTT		splice_acceptor_variant, 5_prime_UTR_truncation, exon_loss_variant, splice_region_variant, intron_variant	Exon 2 of 5	2		ENSP00000424479.1

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Jun 24, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant disrupts a region of the F11 protein in which other variant(s) (p.Cys56Arg) have been determined to be pathogenic (PMID: 11895778, 16079124, 20398070, 28960694). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This sequence change affects the initiator methionine of the F11 mRNA. The next in-frame methionine is located at codon 120. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with F11-related conditions. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.9

Splicing

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

Other links and lift over

hg19: chr4-187188283;