4-186276299-G-T

Variant names:

• chr4-186276299-G-T
• rs281875245
• NM_000128.4:c.664G>T

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_000128.4(F11):​c.664G>T​(p.Asp222Tyr) variant causes a missense change. 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D222E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: F11 NM_000128.4 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 6.52
• Publications: 3 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 17 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000128.4
• PM2: Very rare variant in population databases, with high coverage
• 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, 0.973
• PP5: Variant 4-186276299-G-T is Pathogenic according to our data. Variant chr4-186276299-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 68195.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000128.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F11	NM_000128.4	MANE Select	c.664G>T	p.Asp222Tyr	missense	Exon 7 of 15	NP_000119.1
	F11	NM_001440590.1		c.664G>T	p.Asp222Tyr	missense	Exon 7 of 15	NP_001427519.1
	F11	NM_001440593.1		c.664G>T	p.Asp222Tyr	missense	Exon 7 of 14	NP_001427522.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F11	ENST00000403665.7	TSL:1 MANE Select	c.664G>T	p.Asp222Tyr	missense	Exon 7 of 15	ENSP00000384957.2
	F11	ENST00000452239.1	TSL:5	c.109G>T	p.Asp37Tyr	missense	Exon 2 of 6	ENSP00000397401.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary factor XI deficiency disease Pathogenic:2

Apr 08, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 01, 2019

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

not provided Other:1

UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.91	D
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		6.5
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.75		Gain of loop (P = 0.0312)
MVP		0.97
MPC		0.56
ClinPred		1.0	D
GERP RS		5.5
PromoterAI		-0.042	Neutral
Varity_R		0.98
gMVP		0.93
Mutation Taster		=9/91	disease causing (ClinVar)

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: rs281875245; hg19: chr4-187197453;