rs755377592

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PP2PP3_StrongPP5_Moderate

The NM_019616.4(F7):c.1219G>A(p.Ala407Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000198 in 1,612,338 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 (★). Synonymous variant affecting the same amino acid position (i.e. A407A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

F7
NM_019616.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:3

Conservation

PhyloP100: 6.70

Publications

4 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: Likely_pathogenic. The variant received 7 ACMG points.

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, 0.965

PP5

Variant 13-113118892-G-A is Pathogenic according to our data. Variant chr13-113118892-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 374352.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F7	NM_019616.4 link	c.1219G>A	p.Ala407Thr	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.1219G>A	p.Ala407Thr	missense_variant	Exon 8 of 8	1	NM_019616.4	ENSP00000329546.4	P08709-2
F7	ENST00000375581.3 link	c.1285G>A	p.Ala429Thr	missense_variant	Exon 9 of 9	1		ENSP00000364731.3	P08709-1
F7	ENST00000541084.5 link	c.1033G>A	p.Ala345Thr	missense_variant	Exon 6 of 6	2		ENSP00000442051.2	F5H8B0

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000765

AC:

AN:

248338

AF XY:

0.0000740

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000406

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000449

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000205

AC:

AN:

1460138

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

726316

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33474

American (AMR)

AF:

0.000358

AC:

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26106

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86238

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52012

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000126

AC:

AN:

1111778

Other (OTH)

AF:

0.00

AC:

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152200

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41460

American (AMR)

AF:

0.0000654

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000577

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

Pathogenic:1

Mar 27, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Factor VII deficiency

Pathogenic:1

Jun 30, 2014

Baylor Genetics

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Our laboratory reported dual molecular diagnoses in F7 (NM_000131.4, c.1285G>A) and MECP2 (NM_004992.3, c.332G>A) in this individual with reported features of motor delay, intellectual disability, hypotonia, bilateral sensorineural hearing loss, skeletal abnormalities, hypertrichosis, and factor VII deficiency. The F7 variant has been previously found in patients with Factor VII deficiency (FA7D) [MIM:227500] (PMID 18976247), and is considered likely pathogenic. The patient's mother was similarly affected with factor VII deficiency and was homozygous for the variant. Heterozygotes are expected to be asymptomatic carriers. -

F7-related disorder

Pathogenic:1

Dec 26, 2023

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The F7 c.1285G>A variant is predicted to result in the amino acid substitution p.Ala429Thr. This variant (aka p.Ala369Thr) has been reported in individuals with Factor VII deficiency (Herrmann et al 2009. PubMed ID: 18976247; Ravanbod et al. 2022. PubMed ID: 36760778; Pshenichnikova et al. 2023. PubMed ID: 37761907). A different missense substitution at this same codon (c.1286C>T, Ala429Val) has been reported in an individual with factor VII deficiency (Tang et al. 2022. PubMed ID: 35349734) suggesting that substitution of amino acid residue Ala429 is not tolerated. This variant is reported in 0.041% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.64

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.82

.;.;D

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.84

T;T;T

M_CAP

Pathogenic

0.54

MetaRNN

Pathogenic

0.96

D;D;D

MetaSVM

Uncertain

0.65

MutationAssessor

Benign

1.9

.;.;M

PhyloP100

6.7

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-3.5

.;D;D

REVEL

Pathogenic

0.77

Sift

Uncertain

0.0060

.;D;D

Sift4G

Uncertain

0.0060

D;D;D

Polyphen

1.0

.;D;D

Vest4

0.77

MutPred

0.77

.;.;Gain of catalytic residue at T430 (P = 0);

MVP

0.90

MPC

0.73

ClinPred

0.72

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.91

gMVP

0.94

Mutation Taster

=10/90

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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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