chr4-186267129-ATTGTAGGATGATTTTC-A

Position:

• chr4-186267129-ATTGTAGGATGATTTTC-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000128.4(F11):​c.-1-4_11del variant causes a splice acceptor, coding sequence, 5 prime UTR, intron change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: F11 NM_000128.4 splice_acceptor, coding_sequence, 5_prime_UTR, intron
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.94

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 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 4.4, offset of -23, new splice context is: tacattttatgttctaaaAGcat. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• 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/exons	MANE	UniProt
F11	NM_000128.4	c.-1-4_11del		splice_acceptor_variant, coding_sequence_variant, 5_prime_UTR_variant, intron_variant	2/15	ENST00000403665.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F11	ENST00000403665.7	c.-1-4_11del		splice_acceptor_variant, coding_sequence_variant, 5_prime_UTR_variant, intron_variant	2/15	1	NM_000128.4	P1
F11	ENST00000492972.6	c.-1-4_11del		splice_acceptor_variant, coding_sequence_variant, 5_prime_UTR_variant, intron_variant	2/5	2

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 24, 2023

For these reasons, this variant has been classified as Pathogenic. 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant has not been reported in the literature in individuals affected with F11-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the F11 mRNA. The next in-frame methionine is located at codon 120. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-187188283;