4-186266940-T-G

Variant names:

• chr4-186266940-T-G
• rs4253399
• NM_000128.4:c.-1-196T>G

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.-1-196T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.304 in 151,496 control chromosomes in the GnomAD database, including 8,129 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.30 (8129 hom., cov: 30)
• Consequence: F11 NM_000128.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.847
• Publications: 31 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=-0.91).
• BP6: Variant 4-186266940-T-G is Benign according to our data. Variant chr4-186266940-T-G is described in ClinVar as [Benign]. Clinvar id is 1296768.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.383 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F11	NM_000128.4	c.-1-196T>G		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.-1-196T>G		intron_variant	Intron 1 of 14	1	NM_000128.4	ENSP00000384957.2
F11	ENST00000492972.6	c.-1-196T>G		intron_variant	Intron 1 of 4	2		ENSP00000424479.1

Frequencies

GnomAD3 genomes AF: 0.305 AC: 46115 AN: 151380 Hom.: 8122 Cov.: 30

Gnomad AFR AF: 0.112

Gnomad AMI AF: 0.481

Gnomad AMR AF: 0.348

Gnomad ASJ AF: 0.358

Gnomad EAS AF: 0.332

Gnomad SAS AF: 0.290

Gnomad FIN AF: 0.415

Gnomad MID AF: 0.320

Gnomad NFE AF: 0.387

Gnomad OTH AF: 0.342

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

GnomAD4 genome AF: 0.304 AC: 46129 AN: 151496 Hom.: 8129 Cov.: 30 AF XY: 0.305 AC XY: 22595 AN XY: 73968

African (AFR) AF: 0.112 AC: 4600 AN: 41238

American (AMR) AF: 0.348 AC: 5309 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.358 AC: 1238 AN: 3462

East Asian (EAS) AF: 0.332 AC: 1692 AN: 5102

South Asian (SAS) AF: 0.290 AC: 1376 AN: 4748

European-Finnish (FIN) AF: 0.415 AC: 4352 AN: 10490

Middle Eastern (MID) AF: 0.330 AC: 97 AN: 294

European-Non Finnish (NFE) AF: 0.387 AC: 26300 AN: 67914

Other (OTH) AF: 0.347 AC: 726 AN: 2094

Alfa AF: 0.349 Hom.: 20215

Bravo AF: 0.291

Asia WGS AF: 0.327 AC: 1137 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

May 11, 2021

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	-0.91
CADD	Benign	0.73
DANN	Benign	0.42
PhyloP100		-0.85
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: rs4253399; hg19: chr4-187188094;