rs5973

chr4-186274219-C-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.429C>T(p.Asp143=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.034 in 1,614,124 control chromosomes in the GnomAD database, including 1,649 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.061 (537 hom., cov: 32)
  • Exomes 𝑓: 0.031 (1112 hom.)
• Consequence: F11 NM_000128.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.381

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=-0.73).
• BP6: Variant 4-186274219-C-T is Benign according to our data. Variant chr4-186274219-C-T is described in ClinVar as [Benign]. Clinvar id is 255180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186274219-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.381 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.144 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
F11	NM_000128.4	c.429C>T	p.Asp143=	synonymous_variant	5/15	ENST00000403665.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F11	ENST00000403665.7	c.429C>T	p.Asp143=	synonymous_variant	5/15	1	NM_000128.4	P1
F11	ENST00000492972.6	c.429C>T	p.Asp143=	synonymous_variant	5/5	2
F11	ENST00000514715.1	n.301C>T		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes AF: 0.0609 AC: 9268 AN: 152134 Hom.: 534 Cov.: 32

Gnomad AFR AF: 0.147

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0367

Gnomad ASJ AF: 0.0323

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00827

Gnomad FIN AF: 0.0211

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0306

Gnomad OTH AF: 0.0569

GnomAD3 exomes AF: 0.0325 AC: 8169 AN: 251264 Hom.: 301 AF XY: 0.0298 AC XY: 4048 AN XY: 135790

Gnomad AFR exome AF: 0.154

Gnomad AMR exome AF: 0.0242

Gnomad ASJ exome AF: 0.0328

Gnomad EAS exome AF: 0.000217

Gnomad SAS exome AF: 0.00928

Gnomad FIN exome AF: 0.0202

Gnomad NFE exome AF: 0.0314

Gnomad OTH exome AF: 0.0350

GnomAD4 exome AF: 0.0312 AC: 45558 AN: 1461872 Hom.: 1112 Cov.: 32 AF XY: 0.0300 AC XY: 21844 AN XY: 727236

Gnomad4 AFR exome AF: 0.155

Gnomad4 AMR exome AF: 0.0271

Gnomad4 ASJ exome AF: 0.0349

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00944

Gnomad4 FIN exome AF: 0.0201

Gnomad4 NFE exome AF: 0.0304

Gnomad4 OTH exome AF: 0.0372

GnomAD4 genome AF: 0.0609 AC: 9279 AN: 152252 Hom.: 537 Cov.: 32 AF XY: 0.0594 AC XY: 4419 AN XY: 74448

Gnomad4 AFR AF: 0.147

Gnomad4 AMR AF: 0.0366

Gnomad4 ASJ AF: 0.0323

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00787

Gnomad4 FIN AF: 0.0211

Gnomad4 NFE AF: 0.0307

Gnomad4 OTH AF: 0.0558

Alfa AF: 0.0456 Hom.: 152

Bravo AF: 0.0674

Asia WGS AF: 0.0150 AC: 55 AN: 3478

EpiCase AF: 0.0334

EpiControl AF: 0.0344

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 03, 2020	The p.Asp134Asp variant in F11 is classified as benign because it does not alter an amino acid residue, is not located within the splice consensus site, and computational splice prediction tools do not predict an impact on splicing. It has been identified in 15.2% (3789/24956) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BA1, BP4, BP7. -

Hereditary factor XI deficiency disease Benign:1

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Plasma factor XI deficiency Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Nov 22, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
Cadd	Benign	5.1
Dann	Benign	0.42

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: rs5973; hg19: chr4-187195373; COSMIC: COSV53010481; COSMIC: COSV53010481;