13-113118772-T-G

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong

The NM_019616.4(F7):c.1099T>G(p.Cys367Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,460,948 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

F7
NM_019616.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 6.04

Publications

6 publications found

Variant links:

Genes affected

F7 (HGNC:3544): (coagulation factor VII) This gene encodes coagulation factor VII which is a vitamin K-dependent factor essential for hemostasis. This factor circulates in the blood in a zymogen form, and is converted to an active form by either factor IXa, factor Xa, factor XIIa, or thrombin by minor proteolysis. Upon activation of the factor VII, a heavy chain containing a catalytic domain and a light chain containing 2 EGF-like domains are generated, and two chains are held together by a disulfide bond. In the presence of factor III and calcium ions, the activated factor then further activates the coagulation cascade by converting factor IX to factor IXa and/or factor X to factor Xa. Defects in this gene can cause coagulopathy. Alternative splicing results in multiple transcript variants encoding different isoforms that may undergo similar proteolytic processing to generate mature polypeptides. [provided by RefSeq, Aug 2015]

F7 Gene-Disease associations (from GenCC):

congenital factor VII deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Orphanet, Ambry Genetics
factor VII deficiency
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

F7 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 17 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_019616.4

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 39 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. Gene score misZ: 0.31991 (below the threshold of 3.09). Trascript score misZ: 0.36088 (below the threshold of 3.09). GenCC associations: The gene is linked to congenital factor VII deficiency, factor VII deficiency.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.99

PP5

Variant 13-113118772-T-G is Pathogenic according to our data. Variant chr13-113118772-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 12085.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F7	NM_019616.4 link	c.1099T>G	p.Cys367Gly	missense_variant	Exon 8 of 8	ENST00000346342.8	NP_062562.1	P08709-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
F7	ENST00000346342.8 link	c.1099T>G	p.Cys367Gly	missense_variant	Exon 8 of 8	1	NM_019616.4	ENSP00000329546.4	P08709-2
F7	ENST00000375581.3 link	c.1165T>G	p.Cys389Gly	missense_variant	Exon 9 of 9	1		ENSP00000364731.3	P08709-1
F7	ENST00000541084.5 link	c.913T>G	p.Cys305Gly	missense_variant	Exon 6 of 6	2		ENSP00000442051.2	F5H8B0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000401

AC:

AN:

249480

AF XY:

0.0000369

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000545

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1460948

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726772

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.000126

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52568

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111978

Other (OTH)

AF:

0.00

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Congenital factor VII deficiency

Pathogenic:2

Jun 17, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: F7 c.1165T>G (p.Cys389Gly) results in a non-conservative amino acid change located in the Serine proteases, trypsin domain (IPR001254) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 249480 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in F7 causing Congenital factor VII deficiency, allowing no conclusion about variant significance. c.1165T>G has been reported in the literature in multiple individuals affected with Congenital factor VII deficiency (e.g. Yu_2009, Kwon_2011). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 19601987, 21206266). ClinVar contains an entry for this variant (Variation ID: 12085). Based on the evidence outlined above, the variant was classified as pathogenic. -

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM2_Supporting+PP3_Moderate+PM3+PP4 -

Congenital factor VII deficiency;C1832662:Myocardial infarction, susceptibility to

Pathogenic:1

Jun 18, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Factor VII deficiency

Pathogenic:1

Oct 01, 2000

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Pathogenic

0.42

CADD

Pathogenic

(source)

DANN

Benign

0.97

DEOGEN2

Pathogenic

0.96

.;.;D

Eigen

Pathogenic

0.74

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.64

T;T;T

M_CAP

Pathogenic

0.77

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.6

.;.;H

PhyloP100

6.0

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-12

.;D;D

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

.;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

.;D;D

Vest4

0.95

MutPred

0.89

.;.;Gain of catalytic residue at S393 (P = 0);

MVP

0.98

MPC

0.83

ClinPred

1.0

GERP RS

4.1

Varity_R

0.98

gMVP

0.99

Mutation Taster

=0/100

disease causing (ClinVar)

(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

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13-113118772-T-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over