rs3822057

Positions:

• chr4-186266998-A-C
• chr4-186266998-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000128.4(F11):​c.-1-138A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.51 in 679,264 control chromosomes in the GnomAD database, including 89,535 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.53 (21225 hom., cov: 32)
  • Exomes 𝑓: 0.51 (68310 hom.)
• Consequence: F11 NM_000128.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.129

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 4-186266998-A-C is Benign according to our data. Variant chr4-186266998-A-C is described in ClinVar as [Benign]. Clinvar id is 1185146.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.603 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
F11	NM_000128.4	c.-1-138A>C		intron_variant		ENST00000403665.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F11	ENST00000403665.7	c.-1-138A>C		intron_variant		1	NM_000128.4	P1
F11	ENST00000492972.6	c.-1-138A>C		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.525 AC: 79788 AN: 151838 Hom.: 21194 Cov.: 32

Gnomad AFR AF: 0.560

Gnomad AMI AF: 0.520

Gnomad AMR AF: 0.530

Gnomad ASJ AF: 0.432

Gnomad EAS AF: 0.622

Gnomad SAS AF: 0.446

Gnomad FIN AF: 0.581

Gnomad MID AF: 0.408

Gnomad NFE AF: 0.499

Gnomad OTH AF: 0.521

GnomAD4 exome AF: 0.506 AC: 266661 AN: 527306 Hom.: 68310 AF XY: 0.500 AC XY: 141823 AN XY: 283520

Gnomad4 AFR exome AF: 0.552

Gnomad4 AMR exome AF: 0.563

Gnomad4 ASJ exome AF: 0.430

Gnomad4 EAS exome AF: 0.602

Gnomad4 SAS exome AF: 0.435

Gnomad4 FIN exome AF: 0.574

Gnomad4 NFE exome AF: 0.497

Gnomad4 OTH exome AF: 0.504

GnomAD4 genome AF: 0.526 AC: 79874 AN: 151958 Hom.: 21225 Cov.: 32 AF XY: 0.526 AC XY: 39090 AN XY: 74258

Gnomad4 AFR AF: 0.560

Gnomad4 AMR AF: 0.530

Gnomad4 ASJ AF: 0.432

Gnomad4 EAS AF: 0.621

Gnomad4 SAS AF: 0.446

Gnomad4 FIN AF: 0.581

Gnomad4 NFE AF: 0.499

Gnomad4 OTH AF: 0.524

Alfa AF: 0.437 Hom.: 2283

Bravo AF: 0.523

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary factor XI deficiency disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 10, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.90
DANN	Benign	0.68

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: rs3822057; hg19: chr4-187188152;