4-186266998-A-C

Variant names:

• chr4-186266998-A-C
• rs3822057
• NM_000128.4:c.-1-138A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000128.4(F11):​c.-1-138A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.51 in 679,264 control chromosomes in the GnomAD database, including 89,535 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.53 (21225 hom., cov: 32)
  • Exomes 𝑓: 0.51 (68310 hom.)
• Consequence: F11 NM_000128.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.129
• Publications: 9 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 4-186266998-A-C is Benign according to our data. Variant chr4-186266998-A-C is described in ClinVar as Benign. ClinVar VariationId is 1185146.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.603 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F11	NM_000128.4	MANE Select	c.-1-138A>C		intron	N/A	NP_000119.1
	F11	NM_001440590.1		c.-1-138A>C		intron	N/A	NP_001427519.1
	F11	NM_001440593.1		c.-1-138A>C		intron	N/A	NP_001427522.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F11	ENST00000403665.7	TSL:1 MANE Select	c.-1-138A>C		intron	N/A	ENSP00000384957.2
	F11	ENST00000492972.6	TSL:2	c.-1-138A>C		intron	N/A	ENSP00000424479.1

Frequencies

GnomAD3 genomes AF: 0.525 AC: 79788 AN: 151838 Hom.: 21194 Cov.: 32

Gnomad AFR AF: 0.560

Gnomad AMI AF: 0.520

Gnomad AMR AF: 0.530

Gnomad ASJ AF: 0.432

Gnomad EAS AF: 0.622

Gnomad SAS AF: 0.446

Gnomad FIN AF: 0.581

Gnomad MID AF: 0.408

Gnomad NFE AF: 0.499

Gnomad OTH AF: 0.521

GnomAD4 exome AF: 0.506 AC: 266661 AN: 527306 Hom.: 68310 AF XY: 0.500 AC XY: 141823 AN XY: 283520

African (AFR) AF: 0.552 AC: 8212 AN: 14888

American (AMR) AF: 0.563 AC: 18084 AN: 32144

Ashkenazi Jewish (ASJ) AF: 0.430 AC: 7620 AN: 17708

East Asian (EAS) AF: 0.602 AC: 19016 AN: 31602

South Asian (SAS) AF: 0.435 AC: 24453 AN: 56278

European-Finnish (FIN) AF: 0.574 AC: 22001 AN: 38320

Middle Eastern (MID) AF: 0.421 AC: 944 AN: 2240

European-Non Finnish (NFE) AF: 0.497 AC: 151774 AN: 305226

Other (OTH) AF: 0.504 AC: 14557 AN: 28900

GnomAD4 genome AF: 0.526 AC: 79874 AN: 151958 Hom.: 21225 Cov.: 32 AF XY: 0.526 AC XY: 39090 AN XY: 74258

African (AFR) AF: 0.560 AC: 23199 AN: 41440

American (AMR) AF: 0.530 AC: 8094 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.432 AC: 1499 AN: 3468

East Asian (EAS) AF: 0.621 AC: 3209 AN: 5164

South Asian (SAS) AF: 0.446 AC: 2144 AN: 4812

European-Finnish (FIN) AF: 0.581 AC: 6126 AN: 10542

Middle Eastern (MID) AF: 0.422 AC: 124 AN: 294

European-Non Finnish (NFE) AF: 0.499 AC: 33899 AN: 67936

Other (OTH) AF: 0.524 AC: 1106 AN: 2112

Alfa AF: 0.499 Hom.: 7788

Bravo AF: 0.523

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary factor XI deficiency disease Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.90
DANN	Benign	0.68
PhyloP100		0.13
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: rs3822057; hg19: chr4-187188152;