rs281875249

Variant names:

• chr4-186286475-G-T
• rs281875249
• NM_000128.4:c.1541G>T

Your query was ambiguous. Multiple possible variants found:

• chr4-186286475-G-T
• chr4-186286475-G-A

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Strong

The NM_000128.4(F11):​c.1541G>T​(p.Cys514Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,674 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: F11 NM_000128.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 7.35
• Publications: 1 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-AS1 (HGNC:27725): (F11 antisense RNA 1)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 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, 0.972

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F11	NM_000128.4	MANE Select	c.1541G>T	p.Cys514Phe	missense	Exon 13 of 15	NP_000119.1	P03951-1
	F11	NM_001440590.1		c.1493G>T	p.Cys498Phe	missense	Exon 13 of 15	NP_001427519.1
	F11	NM_001440605.1		c.1271G>T	p.Cys424Phe	missense	Exon 11 of 13	NP_001427534.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F11	ENST00000403665.7	TSL:1 MANE Select	c.1541G>T	p.Cys514Phe	missense	Exon 13 of 15	ENSP00000384957.2	P03951-1
	F11-AS1	ENST00000505103.5	TSL:1	n.1006-209C>A		intron	N/A
	F11	ENST00000886339.1		c.1541G>T	p.Cys514Phe	missense	Exon 13 of 15	ENSP00000556398.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461674 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727144

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53386

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111872

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)
-	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.83	D
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		7.4
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-9.1	D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.79		Gain of MoRF binding (P = 0.0853)
MVP		0.99
MPC		0.62
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.97
gMVP		0.96
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs281875249; hg19: chr4-187207629;