NM_000128.4:c.56-282T>C

Variant names:

• chr4-186271327-T-C
• rs2036914
• NM_000128.4:c.56-282T>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.56-282T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.574 in 152,080 control chromosomes in the GnomAD database, including 25,471 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.57 (25471 hom., cov: 32)
• Consequence: F11 NM_000128.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.295
• Publications: 86 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=-0.88).
• BP6: Variant 4-186271327-T-C is Benign according to our data. Variant chr4-186271327-T-C is described in ClinVar as Benign. ClinVar VariationId is 1262979.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.756 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F11	NM_000128.4	c.56-282T>C		intron_variant	Intron 2 of 14	ENST00000403665.7	NP_000119.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F11	ENST00000403665.7	c.56-282T>C		intron_variant	Intron 2 of 14	1	NM_000128.4	ENSP00000384957.2
F11	ENST00000492972.6	c.56-282T>C		intron_variant	Intron 2 of 4	2		ENSP00000424479.1

Frequencies

GnomAD3 genomes AF: 0.574 AC: 87161 AN: 151962 Hom.: 25435 Cov.: 32

Gnomad AFR AF: 0.642

Gnomad AMI AF: 0.533

Gnomad AMR AF: 0.565

Gnomad ASJ AF: 0.458

Gnomad EAS AF: 0.777

Gnomad SAS AF: 0.459

Gnomad FIN AF: 0.619

Gnomad MID AF: 0.475

Gnomad NFE AF: 0.527

Gnomad OTH AF: 0.578

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

GnomAD4 genome AF: 0.574 AC: 87245 AN: 152080 Hom.: 25471 Cov.: 32 AF XY: 0.575 AC XY: 42781 AN XY: 74338

African (AFR) AF: 0.642 AC: 26632 AN: 41500

American (AMR) AF: 0.565 AC: 8632 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.458 AC: 1585 AN: 3464

East Asian (EAS) AF: 0.777 AC: 4004 AN: 5156

South Asian (SAS) AF: 0.459 AC: 2212 AN: 4822

European-Finnish (FIN) AF: 0.619 AC: 6547 AN: 10576

Middle Eastern (MID) AF: 0.483 AC: 142 AN: 294

European-Non Finnish (NFE) AF: 0.527 AC: 35782 AN: 67960

Other (OTH) AF: 0.581 AC: 1224 AN: 2108

Alfa AF: 0.539 Hom.: 84432

Bravo AF: 0.575

Asia WGS AF: 0.637 AC: 2219 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.4
DANN	Benign	0.59
PhyloP100		-0.29
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: rs2036914; hg19: chr4-187192481;