rs201079681

chr4-186280039-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_000128.4(F11):c.783G>C(p.Glu261Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000979 in 1,613,920 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: F11 NM_000128.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.774

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a domain Apple 3 (size 83) in uniprot entity FA11_HUMAN there are 29 pathogenic changes around while only 2 benign (94%) in NM_000128.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2433078).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
F11	NM_000128.4	c.783G>C	p.Glu261Asp	missense_variant	8/15	ENST00000403665.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F11	ENST00000403665.7	c.783G>C	p.Glu261Asp	missense_variant	8/15	1	NM_000128.4	P1
F11	ENST00000452239.1	c.231G>C	p.Glu77Asp	missense_variant	3/6	5

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152164 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000597 AC: 15 AN: 251328 Hom.: 0 AF XY: 0.0000810 AC XY: 11 AN XY: 135840

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000101 AC: 148 AN: 1461756 Hom.: 0 Cov.: 31 AF XY: 0.000102 AC XY: 74 AN XY: 727182

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000120

Gnomad4 OTH exome AF: 0.0000994

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152164 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74330

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.000478

Bravo AF: 0.0000416

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000659 AC: 8

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary factor XI deficiency disease Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 29, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Dec 28, 2017	- -

Abnormal bleeding Uncertain:1

Uncertain significance, criteria provided, single submitter

research

NIHR Bioresource Rare Diseases, University of Cambridge

Feb 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.064	T
BayesDel_noAF	Uncertain	-0.070
Cadd	Benign	11
Dann	Benign	0.95
DEOGEN2	Uncertain	0.42	T;.
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.49	T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.24	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.4	L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.91	N;.
REVEL	Uncertain	0.53
Sift	Benign	0.16	T;.
Sift4G	Benign	0.43	T;T
Polyphen		0.011	B;.
Vest4		0.32
MutPred		0.72		Loss of sheet (P = 0.0084);.;
MVP		0.93
MPC		0.089
ClinPred		0.020	T
GERP RS		-2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.33
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs201079681; hg19: chr4-187201193;