Genetic Variant NM_000128.4:c.-1-138A>C (chr4-186266998-A-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.129

Publications

9 publications found

Variant links:

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

F11 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F11	NM_000128.4 link	c.-1-138A>C		intron_variant	Intron 1 of 14	ENST00000403665.7	NP_000119.1	P03951-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F11	ENST00000403665.7 link	c.-1-138A>C		intron_variant	Intron 1 of 14	1	NM_000128.4	ENSP00000384957.2		P03951-1
F11	ENST00000492972.6 link	c.-1-138A>C		intron_variant	Intron 1 of 4	2		ENSP00000424479.1		D6RB32

Frequencies

GnomAD3 genomes

AF:

0.525

AC:

79788

AN:

151838

Hom.:

21194

Cov.:

show subpopulations

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

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

6590

13181

19771

26362

32952

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.526

AC:

79874

AN:

151958

Hom.:

21225

Cov.:

AF XY:

0.526

AC XY:

39090

AN XY:

74258

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1913

3826

5738

7651

9564

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.499

Hom.:

7788

Bravo

AF:

0.523

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.90

(source)

DANN

Benign

0.68

PhyloP100

0.13

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

NM_000128.4:c.-1-138A>C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over