rs5967

Variant names:

• chr4-186280373-G-T
• rs5967
• NM_000128.4:c.1016G>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000128.4(F11):​c.1016G>T​(p.Cys339Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0011 in 1,614,182 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0055 (7 hom., cov: 32)
  • Exomes 𝑓: 0.00064 (12 hom.)
• Consequence: F11 NM_000128.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.59
• Publications: 6 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, SD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.007949859).
• BP6: Variant 4-186280373-G-T is Benign according to our data. Variant chr4-186280373-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 348375.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00552 (840/152306) while in subpopulation AFR AF = 0.0188 (781/41560). AF 95% confidence interval is 0.0177. There are 7 homozygotes in GnomAd4. There are 373 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AD,AR,SD gene

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.1016G>T	p.Cys339Phe	missense	Exon 9 of 15	NP_000119.1	P03951-1
	F11	NM_001440590.1		c.968G>T	p.Cys323Phe	missense	Exon 9 of 15	NP_001427519.1
	F11	NM_001440593.1		c.1016G>T	p.Cys339Phe	missense	Exon 9 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.1016G>T	p.Cys339Phe	missense	Exon 9 of 15	ENSP00000384957.2	P03951-1
	F11	ENST00000886358.1		c.1016G>T	p.Cys339Phe	missense	Exon 9 of 16	ENSP00000556417.1
	F11	ENST00000886339.1		c.1016G>T	p.Cys339Phe	missense	Exon 9 of 15	ENSP00000556398.1

Frequencies

GnomAD3 genomes AF: 0.00553 AC: 841 AN: 152188 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0189

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00154 AC: 388 AN: 251452 AF XY: 0.00113

Gnomad AFR exome AF: 0.0205

Gnomad AMR exome AF: 0.000983

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000114

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.000643 AC: 940 AN: 1461876 Hom.: 12 Cov.: 33 AF XY: 0.000543 AC XY: 395 AN XY: 727240

African (AFR) AF: 0.0208 AC: 695 AN: 33480

American (AMR) AF: 0.00145 AC: 65 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: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00381 AC: 22 AN: 5768

European-Non Finnish (NFE) AF: 0.0000603 AC: 67 AN: 1112010

Other (OTH) AF: 0.00147 AC: 89 AN: 60396

GnomAD4 genome AF: 0.00552 AC: 840 AN: 152306 Hom.: 7 Cov.: 32 AF XY: 0.00501 AC XY: 373 AN XY: 74480

African (AFR) AF: 0.0188 AC: 781 AN: 41560

American (AMR) AF: 0.00242 AC: 37 AN: 15296

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000220 AC: 15 AN: 68028

Other (OTH) AF: 0.00284 AC: 6 AN: 2110

Alfa AF: 0.00223 Hom.: 13

Bravo AF: 0.00646

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0170 AC: 75

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00183 AC: 222

Asia WGS AF: 0.000866 AC: 4 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	F11-related disorder (1)
-	-	1	Hereditary factor XI deficiency disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	14
DANN	Benign	0.87
DEOGEN2	Pathogenic	0.90	D
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.0079	T
MetaSVM	Benign	-0.50	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		1.6
PrimateAI	Benign	0.36	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Benign	0.27
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.72	P
Vest4		0.62
MVP		0.93
MPC		0.38
ClinPred		0.11	T
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.57
gMVP		0.85
Mutation Taster		=82/18	polymorphism

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: rs5967; hg19: chr4-187201527;