chr4-186266415-G-A

Variant names:

• chr4-186266415-G-A
• rs925451
• NM_000128.4:c.-2+120G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000128.4(F11):​c.-2+120G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.338 in 152,060 control chromosomes in the GnomAD database, including 9,058 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.34 (9058 hom., cov: 33)
  • Failed GnomAD Quality Control
• Consequence: F11 NM_000128.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00400
• Publications: 12 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 Gene-Disease associations (from GenCC):

• congenital factor XI deficiency

  Inheritance: AR, AD, SD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.385 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.-2+120G>A		intron	N/A	NP_000119.1	P03951-1
	F11	NM_001440590.1		c.-2+120G>A		intron	N/A	NP_001427519.1
	F11	NM_001440593.1		c.-2+120G>A		intron	N/A	NP_001427522.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F11	ENST00000403665.7	TSL:1 MANE Select	c.-2+120G>A		intron	N/A	ENSP00000384957.2	P03951-1
	F11	ENST00000886358.1		c.-2+120G>A		intron	N/A	ENSP00000556417.1
	F11	ENST00000886339.1		c.-1-721G>A		intron	N/A	ENSP00000556398.1

Frequencies

GnomAD3 genomes AF: 0.338 AC: 51289 AN: 151942 Hom.: 9041 Cov.: 33

Gnomad AFR AF: 0.227

Gnomad AMI AF: 0.486

Gnomad AMR AF: 0.358

Gnomad ASJ AF: 0.361

Gnomad EAS AF: 0.331

Gnomad SAS AF: 0.283

Gnomad FIN AF: 0.413

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.389

Gnomad OTH AF: 0.363

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.338 AC: 51339 AN: 152060 Hom.: 9058 Cov.: 33 AF XY: 0.337 AC XY: 25050 AN XY: 74324

African (AFR) AF: 0.228 AC: 9448 AN: 41480

American (AMR) AF: 0.358 AC: 5464 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.361 AC: 1254 AN: 3470

East Asian (EAS) AF: 0.331 AC: 1709 AN: 5170

South Asian (SAS) AF: 0.283 AC: 1364 AN: 4816

European-Finnish (FIN) AF: 0.413 AC: 4367 AN: 10570

Middle Eastern (MID) AF: 0.313 AC: 92 AN: 294

European-Non Finnish (NFE) AF: 0.389 AC: 26422 AN: 67968

Other (OTH) AF: 0.367 AC: 776 AN: 2112

Alfa AF: 0.369 Hom.: 34022

Bravo AF: 0.328

Asia WGS AF: 0.330 AC: 1149 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.0
DANN	Benign	0.65
PhyloP100		-0.0040
PromoterAI		0.0034	Neutral
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: rs925451; hg19: chr4-187187569;