4-186266907-T-C

Variant names:

• chr4-186266907-T-C
• rs4253398
• NM_000128.4:c.-1-229T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000128.4(F11):​c.-1-229T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.221 in 151,906 control chromosomes in the GnomAD database, including 3,970 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.22 (3970 hom., cov: 31)
• Consequence: F11 NM_000128.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0450
• Publications: 2 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 4-186266907-T-C is Benign according to our data. Variant chr4-186266907-T-C is described in ClinVar as [Benign]. Clinvar id is 1256821.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.249 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F11	NM_000128.4	c.-1-229T>C		intron_variant	Intron 1 of 14	ENST00000403665.7	NP_000119.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F11	ENST00000403665.7	c.-1-229T>C		intron_variant	Intron 1 of 14	1	NM_000128.4	ENSP00000384957.2
F11	ENST00000492972.6	c.-1-229T>C		intron_variant	Intron 1 of 4	2		ENSP00000424479.1

Frequencies

GnomAD3 genomes AF: 0.221 AC: 33564 AN: 151788 Hom.: 3968 Cov.: 31

Gnomad AFR AF: 0.155

Gnomad AMI AF: 0.274

Gnomad AMR AF: 0.242

Gnomad ASJ AF: 0.379

Gnomad EAS AF: 0.253

Gnomad SAS AF: 0.221

Gnomad FIN AF: 0.165

Gnomad MID AF: 0.389

Gnomad NFE AF: 0.252

Gnomad OTH AF: 0.263

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

GnomAD4 genome AF: 0.221 AC: 33593 AN: 151906 Hom.: 3970 Cov.: 31 AF XY: 0.218 AC XY: 16188 AN XY: 74250

African (AFR) AF: 0.155 AC: 6422 AN: 41450

American (AMR) AF: 0.243 AC: 3700 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.379 AC: 1314 AN: 3470

East Asian (EAS) AF: 0.253 AC: 1303 AN: 5142

South Asian (SAS) AF: 0.221 AC: 1058 AN: 4790

European-Finnish (FIN) AF: 0.165 AC: 1737 AN: 10546

Middle Eastern (MID) AF: 0.378 AC: 111 AN: 294

European-Non Finnish (NFE) AF: 0.252 AC: 17146 AN: 67940

Other (OTH) AF: 0.262 AC: 552 AN: 2108

Alfa AF: 0.231 Hom.: 644

Bravo AF: 0.230

Asia WGS AF: 0.214 AC: 745 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.2
DANN	Benign	0.66
PhyloP100		-0.045
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: rs4253398; hg19: chr4-187188061;