13-113118716-G-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_019616.4(F7):c.1043G>T(p.Cys348Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000366 in 1,613,040 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: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

F7
NM_019616.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 7.47

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a chain Factor VII heavy chain (size 253) in uniprot entity FA7_HUMAN there are 72 pathogenic changes around while only 5 benign (94%) in NM_019616.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.985

PP5

Variant 13-113118716-G-T is Pathogenic according to our data. Variant chr13-113118716-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 265135.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-113118716-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F7	NM_019616.4 link	c.1043G>T	p.Cys348Phe	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.1043G>T	p.Cys348Phe	missense_variant	Exon 8 of 8	1	NM_019616.4	ENSP00000329546.4	P08709-2
F7	ENST00000375581.3 link	c.1109G>T	p.Cys370Phe	missense_variant	Exon 9 of 9	1		ENSP00000364731.3	P08709-1
F7	ENST00000541084.5 link	c.857G>T	p.Cys286Phe	missense_variant	Exon 6 of 6	2		ENSP00000442051.2	F5H8B0

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000643

AC:

AN:

248908

Hom.:

AF XY:

0.0000961

AC XY:

AN XY:

135286

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000458

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000893

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.0000397

AC:

AN:

1460754

Hom.:

Cov.:

AF XY:

0.0000619

AC XY:

AN XY:

726670

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000394

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000189

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152286

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000306

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Factor VII deficiency

Pathogenic:3

Aug 07, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 01, 1992

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Feb 01, 2019

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Congenital factor VII deficiency

Pathogenic:3

Oct 07, 2022

Genetics and Molecular Pathology, SA Pathology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The F7 c.1043G>T variant is classified as LIKELY PATHOGENIC (PM2, PP3-mod, PM1, PM3, PP4). The F7 c.1043G>T variant is a single nucleotide substitution in exon 8/8 of the F7 gene, which is predicted to change the cysteine at position 348 in the protein the phenylalanine. This variant is in dbSNP (rs121964927) and is present in population databases at very low frequency (gnomAD 0.0013%, AR) (PM2). Computational predictions support a deleterious effect on the gene or gene product (PP3-Moderate). This variant is located in a critical well-established functional domain (PM1). This variant was detected in trans with a likely pathogenic variant (PM3). The patient’s phenotype is highly specific for a disease with a single genetic aetiology (biochemical functional assay show low FVII activity) (PP4). -

Mar 29, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:2

May 20, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 22, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate reduced activity of secreted FVII, decreased binding to tissue factor, and reduced activation by FXa compared to wild-type (Fromovich-Amit, et al., 2004); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34598035, 34426522, 28447100, 31064749, 1634227, 31589614, 10959697, 11313743, 8043443, 18976247, 11129332, 8883260, 15456489) -

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

Pathogenic:1

Apr 03, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

See cases

Pathogenic:1

Nov 13, 2020

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PS4, PM2, PM3, PP3 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Pathogenic

0.43

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.96

.;.;D

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.77

T;T;T

M_CAP

Pathogenic

0.41

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.4

.;.;M

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-8.8

.;D;D

REVEL

Pathogenic

0.89

Sift

Pathogenic

0.0

.;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

.;D;D

Vest4

0.96

MutPred

0.86

.;.;Gain of catalytic residue at C370 (P = 0.0604);

MVP

0.99

MPC

0.93

ClinPred

0.84

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.98

gMVP

0.99

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over