chr4-186271712-C-A

Variant names:

• chr4-186271712-C-A
• rs281875261
• NM_000128.4:c.159C>A

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Strong

The NM_000128.4(F11):​c.159C>A​(p.His53Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H53Y) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: F11 NM_000128.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 0.227
• Publications: 2 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 11 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000128.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr4-186271710-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3769443.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 47 curated pathogenic missense variants (we use a threshold of 10). The gene has 7 curated benign missense variants. Gene score misZ: 0.019886 (below the threshold of 3.09). Trascript score misZ: 0.83889 (below the threshold of 3.09). GenCC associations: The gene is linked to congenital factor XI deficiency.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.953

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F11	NM_000128.4	c.159C>A	p.His53Gln	missense_variant	Exon 3 of 15	ENST00000403665.7	NP_000119.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F11	ENST00000403665.7	c.159C>A	p.His53Gln	missense_variant	Exon 3 of 15	1	NM_000128.4	ENSP00000384957.2
F11	ENST00000492972.6	c.159C>A	p.His53Gln	missense_variant	Exon 3 of 5	2		ENSP00000424479.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 03, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: F11 c.159C>A (p.His53Gln) results in a non-conservative amino acid change located in the Apple domain (IPR000177) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251460 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.159C>A has been reported in the literature in the heterozygous state in an individual affected with factor XI deficiency disease (Kim_2012). This report does not provide unequivocal conclusions about association of the variant with Hereditary factor XI deficiency disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 21668437). ClinVar contains an entry for this variant (Variation ID: 68185). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Other:1

-

UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Pathogenic	0.86	D;D;.
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Uncertain	0.74	D
MutationAssessor	Uncertain	2.8	M;.;M
PhyloP100		0.23
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.4	D;D;D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.78
MutPred		0.74		Loss of helix (P = 0.0626);Loss of helix (P = 0.0626);Loss of helix (P = 0.0626);
MVP		0.99
MPC		0.51
ClinPred		0.97	D
GERP RS		-0.53
Varity_R		0.79
gMVP		0.89
Mutation Taster		=7/93	disease causing

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

Other links and lift over

dbSNP: rs281875261; hg19: chr4-187192866;