rs5974

Positions:

• chr4-186280057-A-G
• chr4-186280057-A-T

Variant summary

Our verdict is Benign. Variant got -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

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 4-186280057-A-G is Benign according to our data. Variant chr4-186280057-A-G is described in ClinVar 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 Lovd as [Benign].
• 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/exons	MANE	Protein	UniProt
F11	NM_000128.4	c.801A>G	p.Thr267Thr	synonymous_variant	8/15	ENST00000403665.7	NP_000119.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F11	ENST00000403665.7	c.801A>G	p.Thr267Thr	synonymous_variant	8/15	1	NM_000128.4	ENSP00000384957.2
F11	ENST00000452239.1	c.246A>G	p.Thr82Thr	synonymous_variant	3/6	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

GnomAD3 exomes AF: 0.146 AC: 36722 AN: 251312 Hom.: 3029 AF XY: 0.150 AC XY: 20400 AN XY: 135832

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 SAS exome AF: 0.206

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

Gnomad4 AFR exome AF: 0.219

Gnomad4 AMR exome AF: 0.107

Gnomad4 ASJ exome AF: 0.159

Gnomad4 EAS exome AF: 0.0478

Gnomad4 SAS exome AF: 0.204

Gnomad4 FIN exome AF: 0.162

Gnomad4 NFE exome AF: 0.140

Gnomad4 OTH exome AF: 0.149

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

Gnomad4 AFR AF: 0.210

Gnomad4 AMR AF: 0.121

Gnomad4 ASJ AF: 0.149

Gnomad4 EAS AF: 0.0415

Gnomad4 SAS AF: 0.203

Gnomad4 FIN AF: 0.164

Gnomad4 NFE AF: 0.146

Gnomad4 OTH AF: 0.150

Alfa AF: 0.146 Hom.: 3569

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

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Hereditary factor XI deficiency disease Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Plasma factor XI deficiency Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Nov 20, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.62
DANN	Benign	0.33
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

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