rs36209567

Positions:

chr13-113118668-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PP5_Very_Strong

The NM_019616.4(F7):c.995C>T(p.Ala332Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000401 in 1,612,734 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00036 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00040 ( 0 hom. )

Consequence

F7
NM_019616.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15U:1

Conservation

PhyloP100: 7.22

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:

F7 (HGNC:):

F7 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 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;

PP5

Variant 13-113118668-C-T is Pathogenic according to our data. Variant chr13-113118668-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 12076.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-113118668-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
F7	NM_019616.4 linkuse as main transcript	c.995C>T	p.Ala332Val	missense_variant	8/8	ENST00000346342.8	NP_062562.1	P08709-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
F7	ENST00000346342.8 linkuse as main transcript	c.995C>T	p.Ala332Val	missense_variant	8/8	1	NM_019616.4	ENSP00000329546.4	P08709-2
F7	ENST00000375581.3 linkuse as main transcript	c.1061C>T	p.Ala354Val	missense_variant	9/9	1		ENSP00000364731.3	P08709-1
F7	ENST00000541084.5 linkuse as main transcript	c.809C>T	p.Ala270Val	missense_variant	6/6	2		ENSP00000442051.2	F5H8B0

Frequencies

GnomAD3 genomes

AF:

0.000362

AC:

AN:

152064

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00113

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000559

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000563

AC:

140

AN:

248594

Hom.:

AF XY:

0.000547

AC XY:

AN XY:

135182

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000871

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000933

Gnomad NFE exome

AF:

0.00104

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000405

AC:

591

AN:

1460554

Hom.:

Cov.:

AF XY:

0.000380

AC XY:

276

AN XY:

726586

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000823

Gnomad4 NFE exome

AF:

0.000474

Gnomad4 OTH exome

AF:

0.000248

GnomAD4 genome

AF:

0.000361

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

AN XY:

74404

show subpopulations

Gnomad4 AFR

AF:

0.0000723

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00113

Gnomad4 NFE

AF:

0.000559

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000331

Hom.:

Bravo

AF:

0.000257

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000726

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000474

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 30, 2024	Identified in the homozygous state or with a pathogenic variant on the opposite allele in multiple unrelated patients in the literature (PMID: 15735798, 24533960); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as A294V; This variant is associated with the following publications: (PMID: 24533960, 31064749, 22180436, 7981691, 30431218, 31980526, 31589614, 29431110, 29618153, 33406812, 15735798, 35552711, 36944032, 25582404, 11931672, 18282149, 15456489, 7919338, 10862079) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 01, 2021	This sequence change replaces alanine with valine at codon 354 of the F7 protein (p.Ala354Val). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs36209567, ExAC 0.1%). This missense change has been observed in individuals with factor VII deficiency (PMID: 7919338, 7981691, 10862079, 15735798). It has also been observed to segregate with disease in related individuals. This variant is also known as Ala294Val. ClinVar contains an entry for this variant (Variation ID: 12076). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	F7: PS4, PM2, PS3:Moderate, PP4 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Feb 25, 2021	PS3, PM3_Supporting, PP3 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 16, 2024	PP5, PM3, PS3 -

Factor VII deficiency

Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2000	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Sep 11, 2019	This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PM1,PM2,PP3,PP5. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 15, 2018	The F7 c.1061C>T (p.Ala354Val) missense variant, previously known as p.Ala294Val, has been reported in more than seven studies in which it is found in a total of more than 97 alleles in individuals with factor VII deficiency, including 10 homozygotes and four compound heterozygotes (Bernardi et al. 1994; Wulff et al. 2000; Fromovich-Amit et al. 2004; Mariani et al. 2005; Marty et al. 2008; Branchini et al. 2012; Pavlova et al. 2015). Of note, this variant is also described in cis with a second variant, c.11128delC, in an additional 111 alleles in affected individuals, including 26 individuals homozygous for both variants. The p.Ala354Val variant was absent from 20 controls, but is reported at a frequency of 0.00128 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional analysis of FVII activity in the plasma of a homozygous individual carrying this variant and the second variant, c.11128delC, showed drastically reduced activity. In vivo studies of the p.Ala354Val variant identified decreased activation of FX by variant FVII protein; however, functional studies showed discordant results when evaluating alterations in the variant protein's interaction with activators and cofactors (Toso et al. 2002; Fromovich-Amit et al. 2004; Branchini et al. 2012). Based on the evidence, the p.Ala354Val variant is classified as pathogenic for factor VII deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	research	NIHR Bioresource Rare Diseases, University of Cambridge	Feb 01, 2019	- -

Congenital factor VII deficiency

Pathogenic:3Uncertain:1

Uncertain significance, flagged submission	clinical testing	Revvity Omics, Revvity	Dec 10, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Dec 21, 2023	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with factor VII deficiency (MIM#227500) and myocardial infarction, decreased susceptibility to (MIM#608446). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Patients with the same genotype have been observed with phenotypes ranging from asymptomatic to symptomatic (PMID: 18976247). (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to valine. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (157 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (3 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools. (I) 0600 - Variant is located in the annotated trypsin domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been observed in many homozygote individuals, including individuals homozygote for this variant in cis with p.(Pro442Hisfs*32), and in compound heterozygote individuals, with reduced FVII activity. It has also been reported as pathogenic and likely pathogenic in ClinVar; including one VUS classification (PMID: 18976247). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Oct 07, 2022	The F7 c.995C>T variant is classified as LIKELY PATHOGENIC (PM2_Supporting, PM1, PM3, PP4) The F7 c.995C>T variant is a single nucleotide substitution in exon 8/8 of the F7 gene, which is predicted to change the alanine at position 332 in the protein to valine. This variant is in dbSNP (rs36209567) and is present in population databases at extremely low frequency (0.00002%, AR) (PM2_Supporting). The variant is in a functional domain (PM1). This variant has been reported as homozygous and compound heterozygous and was detected in trans in this patient 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). -

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

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 27, 2022

- -

Abnormal bleeding

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

NIHR Bioresource Rare Diseases, University of Cambridge

Feb 01, 2019

- -

F7-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 13, 2024

The F7 c.1061C>T variant is predicted to result in the amino acid substitution p.Ala354Val. This variant, previously described as p.Ala294Val using legacy nomenclature, has been reported in many patients to be causative for recessive Factor VII Deficiency (see, for example, Wulff et al. 2000. PubMed ID: 10862079; Millar et al. 2000. PubMed ID: 11129332; Mariani et al. 2005. PubMed ID: 15735798; http://F7-db.eahad.org/). This variant is reported in 0.10% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.17

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.76

.;.;D

Eigen

Uncertain

0.21

Eigen_PC

Benign

0.096

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.90

D;D;D

M_CAP

Uncertain

0.24

MetaRNN

Uncertain

0.49

T;T;T

MetaSVM

Uncertain

0.11

MutationAssessor

Benign

0.80

.;.;N

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-3.1

.;D;D

REVEL

Uncertain

0.34

Sift

Uncertain

0.0090

.;D;D

Sift4G

Uncertain

0.010

D;D;D

Polyphen

0.98, 0.98

.;D;D

Vest4

0.21

MVP

0.90

MPC

0.72

ClinPred

0.17

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.73

gMVP

0.84

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