4-186288548-G-T

Variant names:

• chr4-186288548-G-T
• rs5971
• NM_000128.4:c.1812G>T

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.1812G>T​(p.Arg604Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0529 in 1,613,998 control chromosomes in the GnomAD database, including 2,779 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. R604R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.069 (465 hom., cov: 32)
  • Exomes 𝑓: 0.051 (2314 hom.)
• Consequence: F11 NM_000128.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.77
• Publications: 10 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=0.046).
• BP6: Variant 4-186288548-G-T is Benign according to our data. Variant chr4-186288548-G-T is described in ClinVar as Benign. ClinVar VariationId is 255178.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.77 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.113 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.1812G>T	p.Arg604Arg	synonymous	Exon 15 of 15	NP_000119.1	P03951-1
	F11	NM_001440590.1		c.1764G>T	p.Arg588Arg	synonymous	Exon 15 of 15	NP_001427519.1
	F11	NM_001440593.1		c.1716G>T	p.Arg572Arg	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.1812G>T	p.Arg604Arg	synonymous	Exon 15 of 15	ENSP00000384957.2	P03951-1
	F11-AS1	ENST00000505103.5	TSL:1	n.885C>A		non_coding_transcript_exon	Exon 3 of 4
	F11	ENST00000886358.1		c.1998G>T	p.Arg666Arg	synonymous	Exon 16 of 16	ENSP00000556417.1

Frequencies

GnomAD3 genomes AF: 0.0689 AC: 10483 AN: 152072 Hom.: 458 Cov.: 32

Gnomad AFR AF: 0.116

Gnomad AMI AF: 0.0793

Gnomad AMR AF: 0.0599

Gnomad ASJ AF: 0.0816

Gnomad EAS AF: 0.0678

Gnomad SAS AF: 0.0791

Gnomad FIN AF: 0.0382

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.0460

Gnomad OTH AF: 0.0551

GnomAD2 exomes AF: 0.0609 AC: 15323 AN: 251480 AF XY: 0.0604

Gnomad AFR exome AF: 0.118

Gnomad AMR exome AF: 0.0708

Gnomad ASJ exome AF: 0.0814

Gnomad EAS exome AF: 0.0704

Gnomad FIN exome AF: 0.0389

Gnomad NFE exome AF: 0.0464

Gnomad OTH exome AF: 0.0594

GnomAD4 exome AF: 0.0513 AC: 74938 AN: 1461808 Hom.: 2314 Cov.: 31 AF XY: 0.0520 AC XY: 37841 AN XY: 727214

African (AFR) AF: 0.126 AC: 4202 AN: 33468

American (AMR) AF: 0.0701 AC: 3136 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0822 AC: 2149 AN: 26132

East Asian (EAS) AF: 0.0813 AC: 3227 AN: 39700

South Asian (SAS) AF: 0.0775 AC: 6689 AN: 86256

European-Finnish (FIN) AF: 0.0383 AC: 2047 AN: 53414

Middle Eastern (MID) AF: 0.120 AC: 695 AN: 5768

European-Non Finnish (NFE) AF: 0.0444 AC: 49350 AN: 1111952

Other (OTH) AF: 0.0570 AC: 3443 AN: 60394

GnomAD4 genome AF: 0.0691 AC: 10515 AN: 152190 Hom.: 465 Cov.: 32 AF XY: 0.0693 AC XY: 5154 AN XY: 74406

African (AFR) AF: 0.116 AC: 4825 AN: 41534

American (AMR) AF: 0.0604 AC: 923 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0816 AC: 283 AN: 3470

East Asian (EAS) AF: 0.0677 AC: 350 AN: 5168

South Asian (SAS) AF: 0.0794 AC: 382 AN: 4814

European-Finnish (FIN) AF: 0.0382 AC: 405 AN: 10602

Middle Eastern (MID) AF: 0.103 AC: 30 AN: 292

European-Non Finnish (NFE) AF: 0.0460 AC: 3131 AN: 68010

Other (OTH) AF: 0.0541 AC: 114 AN: 2108

Alfa AF: 0.0565 Hom.: 582

Bravo AF: 0.0730

Asia WGS AF: 0.0530 AC: 185 AN: 3478

EpiCase AF: 0.0516

EpiControl AF: 0.0506

ClinVar

ClinVar submissions as Germline

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	-0.61
CADD	Benign	11
DANN	Benign	0.82
PhyloP100		-1.8
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: rs5971; hg19: chr4-187209702; COSMIC: COSV53001568;