chr4-186284190-C-T

Variant names:

• chr4-186284190-C-T
• rs538083600
• NM_000128.4:c.1234C>T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000128.4(F11):​c.1234C>T​(p.Gln412*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,614,228 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: F11 NM_000128.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 1.03
• 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: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 4-186284190-C-T is Pathogenic according to our data. Variant chr4-186284190-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 554679.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186284190-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 554679.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186284190-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 554679.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186284190-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 554679.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186284190-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 554679.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186284190-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 554679.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186284190-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 554679.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186284190-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 554679.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186284190-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 554679.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186284190-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 554679.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186284190-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 554679.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186284190-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 554679.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186284190-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 554679.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186284190-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 554679.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186284190-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 554679.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186284190-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 554679.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186284190-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 554679.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186284190-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 554679.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186284190-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 554679.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186284190-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 554679.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186284190-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 554679.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186284190-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 554679.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186284190-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 554679.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186284190-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 554679.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186284190-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 554679.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186284190-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 554679.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186284190-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 554679.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186284190-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 554679.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186284190-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 554679.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186284190-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 554679.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186284190-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 554679.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F11	NM_000128.4	c.1234C>T	p.Gln412*	stop_gained	Exon 11 of 15	ENST00000403665.7	NP_000119.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F11	ENST00000403665.7	c.1234C>T	p.Gln412*	stop_gained	Exon 11 of 15	1	NM_000128.4	ENSP00000384957.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152216 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461894 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

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

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

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome AF: 0.00000656 AC: 1 AN: 152334 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74488

African (AFR) AF: 0.00 AC: 0 AN: 41572

American (AMR) AF: 0.00 AC: 0 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2112

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary factor XI deficiency disease Pathogenic:4

Oct 31, 2017

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Mar 01, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The stop gained c.1234C>T(p.Gln412Ter) variant in F11 gene has been reported previously in homozygous state in an individual affected with factor XI deficiency (Kawankar N, et. al., 2016). The c.1234C>T variant is novel (not in any individuals) in gnomAD Exomes. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic. The nucleotide change c.1234C>T in F11 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This sequence change creates a premature translational stop signal (p.Gln412Ter) in the F11 gene. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants in F11 gene have been previously reported to be pathogenic (Duga S & Salomon O., 2013). However, additional functional studies will be required to prove the pathogenicity of this variant. -

May 25, 2023

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Nov 13, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Gln412*) in the F11 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in F11 are known to be pathogenic (PMID: 23929304). This variant is present in population databases (rs538083600, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with autosomal recessive factor XI deficiency (PMID: 27710856). This variant is also known as p.Gln394*. ClinVar contains an entry for this variant (Variation ID: 554679). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Uncertain	0.48
Eigen_PC	Benign	0.19
FATHMM_MKL	Benign	0.25	N
PhyloP100		1.0
Vest4		0.83
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs538083600; hg19: chr4-187205344;