chr4-186280057-A-G

Variant names:

• chr4-186280057-A-G
• rs5974
• NM_000128.4:c.801A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000128.4(F11):​c.801A>G​(p.Thr267Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.145 in 1,613,478 control chromosomes in the GnomAD database, including 18,011 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2147 hom., cov: 32)
  • Exomes 𝑓: 0.14 (15864 hom.)
• Consequence: F11 NM_000128.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.38
• Publications: 24 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.013).
• BP6: Variant 4-186280057-A-G is Benign according to our data. Variant chr4-186280057-A-G is described in CliVar as Benign. Clinvar id is 255181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186280057-A-G is described in CliVar as Benign. Clinvar id is 255181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186280057-A-G is described in CliVar as Benign. Clinvar id is 255181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186280057-A-G is described in CliVar as Benign. Clinvar id is 255181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186280057-A-G is described in CliVar as Benign. Clinvar id is 255181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186280057-A-G is described in CliVar as Benign. Clinvar id is 255181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186280057-A-G is described in CliVar as Benign. Clinvar id is 255181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186280057-A-G is described in CliVar as Benign. Clinvar id is 255181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186280057-A-G is described in CliVar as Benign. Clinvar id is 255181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186280057-A-G is described in CliVar as Benign. Clinvar id is 255181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186280057-A-G is described in CliVar as Benign. Clinvar id is 255181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186280057-A-G is described in CliVar as Benign. Clinvar id is 255181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186280057-A-G is described in CliVar as Benign. Clinvar id is 255181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186280057-A-G is described in CliVar as Benign. Clinvar id is 255181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186280057-A-G is described in CliVar as Benign. Clinvar id is 255181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186280057-A-G is described in CliVar as Benign. Clinvar id is 255181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186280057-A-G is described in CliVar as Benign. Clinvar id is 255181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186280057-A-G is described in CliVar as Benign. Clinvar id is 255181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186280057-A-G is described in CliVar as Benign. Clinvar id is 255181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186280057-A-G is described in CliVar as Benign. Clinvar id is 255181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186280057-A-G is described in CliVar as Benign. Clinvar id is 255181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186280057-A-G is described in CliVar as Benign. Clinvar id is 255181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186280057-A-G is described in CliVar as Benign. Clinvar id is 255181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186280057-A-G is described in CliVar as Benign. Clinvar id is 255181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186280057-A-G is described in CliVar as Benign. Clinvar id is 255181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186280057-A-G is described in CliVar as Benign. Clinvar id is 255181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186280057-A-G is described in CliVar as Benign. Clinvar id is 255181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186280057-A-G is described in CliVar as Benign. Clinvar id is 255181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186280057-A-G is described in CliVar as Benign. Clinvar id is 255181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186280057-A-G is described in CliVar as Benign. Clinvar id is 255181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186280057-A-G is described in CliVar as Benign. Clinvar id is 255181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186280057-A-G is described in CliVar as Benign. Clinvar id is 255181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.38 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.206 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F11	NM_000128.4	c.801A>G	p.Thr267Thr	synonymous_variant	Exon 8 of 15	ENST00000403665.7	NP_000119.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F11	ENST00000403665.7	c.801A>G	p.Thr267Thr	synonymous_variant	Exon 8 of 15	1	NM_000128.4	ENSP00000384957.2
F11	ENST00000452239.1	c.246A>G	p.Thr82Thr	synonymous_variant	Exon 3 of 6	5		ENSP00000397401.1

Frequencies

GnomAD3 genomes AF: 0.161 AC: 24525 AN: 152046 Hom.: 2149 Cov.: 32

Gnomad AFR AF: 0.210

Gnomad AMI AF: 0.220

Gnomad AMR AF: 0.122

Gnomad ASJ AF: 0.149

Gnomad EAS AF: 0.0416

Gnomad SAS AF: 0.204

Gnomad FIN AF: 0.164

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.146

Gnomad OTH AF: 0.152

GnomAD2 exomes AF: 0.146 AC: 36722 AN: 251312 AF XY: 0.150

Gnomad AFR exome AF: 0.219

Gnomad AMR exome AF: 0.104

Gnomad ASJ exome AF: 0.160

Gnomad EAS exome AF: 0.0459

Gnomad FIN exome AF: 0.161

Gnomad NFE exome AF: 0.145

Gnomad OTH exome AF: 0.143

GnomAD4 exome AF: 0.143 AC: 209672 AN: 1461314 Hom.: 15864 Cov.: 34 AF XY: 0.146 AC XY: 106230 AN XY: 726990

African (AFR) AF: 0.219 AC: 7328 AN: 33456

American (AMR) AF: 0.107 AC: 4763 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.159 AC: 4162 AN: 26128

East Asian (EAS) AF: 0.0478 AC: 1897 AN: 39698

South Asian (SAS) AF: 0.204 AC: 17606 AN: 86242

European-Finnish (FIN) AF: 0.162 AC: 8634 AN: 53416

Middle Eastern (MID) AF: 0.193 AC: 1112 AN: 5766

European-Non Finnish (NFE) AF: 0.140 AC: 155199 AN: 1111504

Other (OTH) AF: 0.149 AC: 8971 AN: 60386

GnomAD4 genome AF: 0.161 AC: 24530 AN: 152164 Hom.: 2147 Cov.: 32 AF XY: 0.162 AC XY: 12083 AN XY: 74388

African (AFR) AF: 0.210 AC: 8714 AN: 41498

American (AMR) AF: 0.121 AC: 1855 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.149 AC: 516 AN: 3472

East Asian (EAS) AF: 0.0415 AC: 215 AN: 5182

South Asian (SAS) AF: 0.203 AC: 980 AN: 4822

European-Finnish (FIN) AF: 0.164 AC: 1739 AN: 10584

Middle Eastern (MID) AF: 0.211 AC: 62 AN: 294

European-Non Finnish (NFE) AF: 0.146 AC: 9932 AN: 68004

Other (OTH) AF: 0.150 AC: 316 AN: 2110

Alfa AF: 0.147 Hom.: 7889

Bravo AF: 0.157

Asia WGS AF: 0.124 AC: 437 AN: 3476

EpiCase AF: 0.154

EpiControl AF: 0.149

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Nov 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Hereditary factor XI deficiency disease Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Plasma factor XI deficiency Benign:1

Nov 20, 2019

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.62
DANN	Benign	0.33
PhyloP100		-1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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: rs5974; hg19: chr4-187201211; COSMIC: COSV53007052;