chr4-186274219-C-T

Variant names:

• chr4-186274219-C-T
• rs5973
• NM_000128.4:c.429C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000128.4(F11):​c.429C>T​(p.Asp143Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.034 in 1,614,124 control chromosomes in the GnomAD database, including 1,649 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.061 (537 hom., cov: 32)
  • Exomes 𝑓: 0.031 (1112 hom.)
• Consequence: F11 NM_000128.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.381
• Publications: 7 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: AD, AR, SD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 4-186274219-C-T is Benign according to our data. Variant chr4-186274219-C-T is described in ClinVar as Benign. ClinVar VariationId is 255180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.381 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.144 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.429C>T	p.Asp143Asp	synonymous	Exon 5 of 15	NP_000119.1
	F11	NM_001440590.1		c.429C>T	p.Asp143Asp	synonymous	Exon 5 of 15	NP_001427519.1
	F11	NM_001440593.1		c.429C>T	p.Asp143Asp	synonymous	Exon 5 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.429C>T	p.Asp143Asp	synonymous	Exon 5 of 15	ENSP00000384957.2
	F11	ENST00000886358.1		c.429C>T	p.Asp143Asp	synonymous	Exon 5 of 16	ENSP00000556417.1
	F11	ENST00000886339.1		c.429C>T	p.Asp143Asp	synonymous	Exon 5 of 15	ENSP00000556398.1

Frequencies

GnomAD3 genomes AF: 0.0609 AC: 9268 AN: 152134 Hom.: 534 Cov.: 32

Gnomad AFR AF: 0.147

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0367

Gnomad ASJ AF: 0.0323

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00827

Gnomad FIN AF: 0.0211

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0306

Gnomad OTH AF: 0.0569

GnomAD2 exomes AF: 0.0325 AC: 8169 AN: 251264 AF XY: 0.0298

Gnomad AFR exome AF: 0.154

Gnomad AMR exome AF: 0.0242

Gnomad ASJ exome AF: 0.0328

Gnomad EAS exome AF: 0.000217

Gnomad FIN exome AF: 0.0202

Gnomad NFE exome AF: 0.0314

Gnomad OTH exome AF: 0.0350

GnomAD4 exome AF: 0.0312 AC: 45558 AN: 1461872 Hom.: 1112 Cov.: 32 AF XY: 0.0300 AC XY: 21844 AN XY: 727236

African (AFR) AF: 0.155 AC: 5175 AN: 33480

American (AMR) AF: 0.0271 AC: 1212 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0349 AC: 913 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00944 AC: 814 AN: 86258

European-Finnish (FIN) AF: 0.0201 AC: 1076 AN: 53420

Middle Eastern (MID) AF: 0.0609 AC: 351 AN: 5768

European-Non Finnish (NFE) AF: 0.0304 AC: 33768 AN: 1111990

Other (OTH) AF: 0.0372 AC: 2247 AN: 60396

GnomAD4 genome AF: 0.0609 AC: 9279 AN: 152252 Hom.: 537 Cov.: 32 AF XY: 0.0594 AC XY: 4419 AN XY: 74448

African (AFR) AF: 0.147 AC: 6087 AN: 41516

American (AMR) AF: 0.0366 AC: 560 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0323 AC: 112 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00787 AC: 38 AN: 4830

European-Finnish (FIN) AF: 0.0211 AC: 224 AN: 10612

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.0307 AC: 2086 AN: 68020

Other (OTH) AF: 0.0558 AC: 118 AN: 2114

Alfa AF: 0.0463 Hom.: 155

Bravo AF: 0.0674

Asia WGS AF: 0.0150 AC: 55 AN: 3478

EpiCase AF: 0.0334

EpiControl AF: 0.0344

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	5.1
DANN	Benign	0.42
PhyloP100		-0.38
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: rs5973; hg19: chr4-187195373; COSMIC: COSV53010481; COSMIC: COSV53010481;