rs748926718

Variant names:

• chr4-186280548-G-A
• rs748926718
• NM_000128.4:c.1103G>A

Your query was ambiguous. Multiple possible variants found:

• chr4-186280548-G-A
• chr4-186280548-G-C
• chr4-186280548-G-T

Variant summary

Our verdict is Pathogenic. The variant received 23 ACMG points: 23P and 0B. PS3 PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000128.4(F11):​c.1103G>A​(p.Gly368Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000248 in 1,614,024 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 Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV004292792: Experimental studies have shown that this missense change affects F11 function (PMID:15026311)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G368A) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: F11 NM_000128.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 3.75
• 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: AR, AD, SD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 23 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV004292792: Experimental studies have shown that this missense change affects F11 function (PMID: 15026311).; SCV006085533: At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant protein was not secreted, and was not able to form dimers, but had no impact (i.e. had no dominant negative effect) on the secretion of the WT (Kravtsov_2004).
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 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 chr4-186280548-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 551619.
• 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, 0.964
• PP5: Variant 4-186280548-G-A is Pathogenic according to our data. Variant chr4-186280548-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 2734695.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F11	NM_000128.4	MANE Select	c.1103G>A	p.Gly368Glu	missense	Exon 10 of 15	NP_000119.1	P03951-1
	F11	NM_001440590.1		c.1055G>A	p.Gly352Glu	missense	Exon 10 of 15	NP_001427519.1
	F11	NM_001440593.1		c.1103G>A	p.Gly368Glu	missense	Exon 10 of 14	NP_001427522.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F11	ENST00000403665.7	TSL:1 MANE Select	c.1103G>A	p.Gly368Glu	missense	Exon 10 of 15	ENSP00000384957.2	P03951-1
	F11	ENST00000886358.1		c.1103G>A	p.Gly368Glu	missense	Exon 10 of 16	ENSP00000556417.1
	F11	ENST00000886339.1		c.1103G>A	p.Gly368Glu	missense	Exon 10 of 15	ENSP00000556398.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152108 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251366 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461798 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727198

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: 26134

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

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: 1111932

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152226 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74424

African (AFR) AF: 0.00 AC: 0 AN: 41534

American (AMR) AF: 0.00 AC: 0 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2116

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Hereditary factor XI deficiency disease (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.37
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		3.7
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.013	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.85		Loss of sheet (P = 0.0181)
MVP		0.99
MPC		0.57
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.98
gMVP		0.88
Mutation Taster		=1/99	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: rs748926718; hg19: chr4-187201702;