rs5976

Variant names:

• chr4-186288575-G-A
• rs5976
• NM_000128.4:c.1839G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000128.4(F11):​c.1839G>A​(p.Glu613Glu) 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:7
• Conservation: PhyloP100: 0.330
• Publications: 8 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-AS1 (HGNC:27725): (F11 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.041).
• BP6: Variant 4-186288575-G-A is Benign according to our data. Variant chr4-186288575-G-A is described in ClinVar as Benign. ClinVar VariationId is 255179.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000128.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F11	NM_000128.4	MANE Select	c.1839G>A	p.Glu613Glu	synonymous	Exon 15 of 15	NP_000119.1	P03951-1
	F11	NM_001440590.1		c.1791G>A	p.Glu597Glu	synonymous	Exon 15 of 15	NP_001427519.1
	F11	NM_001440593.1		c.1743G>A	p.Glu581Glu	synonymous	Exon 14 of 14	NP_001427522.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F11	ENST00000403665.7	TSL:1 MANE Select	c.1839G>A	p.Glu613Glu	synonymous	Exon 15 of 15	ENSP00000384957.2	P03951-1
	F11-AS1	ENST00000505103.5	TSL:1	n.858C>T		non_coding_transcript_exon	Exon 3 of 4
	F11	ENST00000886358.1		c.2025G>A	p.Glu675Glu	synonymous	Exon 16 of 16	ENSP00000556417.1

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

GnomAD2 exomes AF: 0.0556 AC: 13980 AN: 251436 AF XY: 0.0567

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 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

African (AFR) AF: 0.0428 AC: 1432 AN: 33474

American (AMR) AF: 0.0654 AC: 2926 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0820 AC: 2144 AN: 26134

East Asian (EAS) AF: 0.0813 AC: 3227 AN: 39698

South Asian (SAS) AF: 0.0811 AC: 6992 AN: 86256

European-Finnish (FIN) AF: 0.0383 AC: 2047 AN: 53418

Middle Eastern (MID) AF: 0.114 AC: 660 AN: 5768

European-Non Finnish (NFE) AF: 0.0441 AC: 49074 AN: 1111972

Other (OTH) AF: 0.0512 AC: 3092 AN: 60390

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

African (AFR) AF: 0.0407 AC: 1691 AN: 41566

American (AMR) AF: 0.0533 AC: 815 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0815 AC: 283 AN: 3472

East Asian (EAS) AF: 0.0679 AC: 351 AN: 5172

South Asian (SAS) AF: 0.0812 AC: 391 AN: 4818

European-Finnish (FIN) AF: 0.0382 AC: 405 AN: 10612

Middle Eastern (MID) AF: 0.0925 AC: 27 AN: 292

European-Non Finnish (NFE) AF: 0.0455 AC: 3096 AN: 68034

Other (OTH) AF: 0.0421 AC: 89 AN: 2112

Alfa AF: 0.0491 Hom.: 368

Bravo AF: 0.0483

Asia WGS AF: 0.0480 AC: 165 AN: 3478

EpiCase AF: 0.0510

EpiControl AF: 0.0502

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Hereditary factor XI deficiency disease (2)
-	-	1	not specified (1)
-	-	1	Plasma factor XI deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	15
DANN	Benign	0.87
PhyloP100		0.33
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
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: rs5976; hg19: chr4-187209729; COSMIC: COSV53001582;