rs5976

chr4-186288575-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000128.4(F11):c.1839G>A(p.Glu613=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0488 in 1,614,124 control chromosomes in the GnomAD database, including 2,251 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.047 (192 hom., cov: 32)
  • Exomes 𝑓: 0.049 (2059 hom.)
• Consequence: F11 NM_000128.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.330

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-AS1 (HGNC:27725): (F11 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP6: Variant 4-186288575-G-A is Benign according to our data. Variant chr4-186288575-G-A is described in ClinVar as [Benign]. Clinvar id is 255179.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186288575-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.33 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0745 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
F11	NM_000128.4	c.1839G>A	p.Glu613=	synonymous_variant	15/15	ENST00000403665.7
F11-AS1	NR_033900.1	n.919C>T		non_coding_transcript_exon_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F11	ENST00000403665.7	c.1839G>A	p.Glu613=	synonymous_variant	15/15	1	NM_000128.4	P1
F11-AS1	ENST00000505103.5	n.858C>T		non_coding_transcript_exon_variant	3/4	1
F11	ENST00000264691.4	c.441G>A	p.Glu147=	synonymous_variant	3/3	3
F11	ENST00000503841.1	n.358G>A		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.0474 AC: 7210 AN: 152176 Hom.: 191 Cov.: 32

Gnomad AFR AF: 0.0406

Gnomad AMI AF: 0.0811

Gnomad AMR AF: 0.0527

Gnomad ASJ AF: 0.0815

Gnomad EAS AF: 0.0679

Gnomad SAS AF: 0.0807

Gnomad FIN AF: 0.0382

Gnomad MID AF: 0.0987

Gnomad NFE AF: 0.0455

Gnomad OTH AF: 0.0431

GnomAD3 exomes AF: 0.0556 AC: 13980 AN: 251436 Hom.: 458 AF XY: 0.0567 AC XY: 7699 AN XY: 135890

Gnomad AFR exome AF: 0.0427

Gnomad AMR exome AF: 0.0666

Gnomad ASJ exome AF: 0.0813

Gnomad EAS exome AF: 0.0704

Gnomad SAS exome AF: 0.0799

Gnomad FIN exome AF: 0.0389

Gnomad NFE exome AF: 0.0460

Gnomad OTH exome AF: 0.0564

GnomAD4 exome AF: 0.0490 AC: 71594 AN: 1461830 Hom.: 2059 Cov.: 31 AF XY: 0.0502 AC XY: 36474 AN XY: 727220

Gnomad4 AFR exome AF: 0.0428

Gnomad4 AMR exome AF: 0.0654

Gnomad4 ASJ exome AF: 0.0820

Gnomad4 EAS exome AF: 0.0813

Gnomad4 SAS exome AF: 0.0811

Gnomad4 FIN exome AF: 0.0383

Gnomad4 NFE exome AF: 0.0441

Gnomad4 OTH exome AF: 0.0512

GnomAD4 genome AF: 0.0474 AC: 7222 AN: 152294 Hom.: 192 Cov.: 32 AF XY: 0.0484 AC XY: 3602 AN XY: 74458

Gnomad4 AFR AF: 0.0407

Gnomad4 AMR AF: 0.0533

Gnomad4 ASJ AF: 0.0815

Gnomad4 EAS AF: 0.0679

Gnomad4 SAS AF: 0.0812

Gnomad4 FIN AF: 0.0382

Gnomad4 NFE AF: 0.0455

Gnomad4 OTH AF: 0.0421

Alfa AF: 0.0487 Hom.: 270

Bravo AF: 0.0483

Asia WGS AF: 0.0480 AC: 165 AN: 3478

EpiCase AF: 0.0510

EpiControl AF: 0.0502

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary factor XI deficiency disease Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 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 22, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
Cadd	Benign	15
Dann	Benign	0.87
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6

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: rs5976; hg19: chr4-187209729; COSMIC: COSV53001582;