Genetic Variant F7:p.Leu13His (chr13-113105879-T-A) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PM5PP2

The NM_019616.4(F7):c.38T>A(p.Leu13His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,439,506 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L13P) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

F7
NM_019616.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.991

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr13-113105879-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 12075.Status of the report is no_assertion_criteria_provided, 0 stars.

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F7	NM_019616.4 link	c.38T>A	p.Leu13His	missense_variant	Exon 1 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.38T>A	p.Leu13His	missense_variant	Exon 1 of 8	1	NM_019616.4	ENSP00000329546.4	P08709-2
F7	ENST00000375581.3 link	c.38T>A	p.Leu13His	missense_variant	Exon 1 of 9	1		ENSP00000364731.3	P08709-1
F7	ENST00000541084.5 link	c.38T>A	p.Leu13His	missense_variant	Exon 1 of 6	2		ENSP00000442051.2	F5H8B0
F7	ENST00000444337.1 link	n.38T>A		non_coding_transcript_exon_variant	Exon 1 of 5	5		ENSP00000387669.1	E9PH36

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000462

AC:

AN:

216450

AF XY:

0.00000862

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000139

AC:

AN:

1439506

Hom.:

Cov.:

AF XY:

0.00000280

AC XY:

AN XY:

713336

show subpopulations

Gnomad4 AFR exome

AF:

0.00

AC:

AN:

33380

Gnomad4 AMR exome

AF:

0.00

AC:

AN:

41510

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

25492

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39124

Gnomad4 SAS exome

AF:

0.0000243

AC:

AN:

82192

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

50650

Gnomad4 NFE exome

AF:

0.00

AC:

AN:

1101768

Gnomad4 Remaining exome

AF:

0.00

AC:

AN:

59656

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

-0.050

CADD

Uncertain

DANN

Benign

0.80

DEOGEN2

Uncertain

0.54

.;.;D

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.61

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.32

T;T;T

M_CAP

Uncertain

0.15

MetaRNN

Uncertain

0.52

D;D;D

MetaSVM

Uncertain

-0.090

MutationAssessor

Uncertain

2.2

.;M;M

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-2.1

.;N;N

REVEL

Uncertain

0.38

Sift

Uncertain

0.019

.;D;D

Sift4G

Pathogenic

0.0

D;T;D

Polyphen

1.0, 1.0

.;D;D

Vest4

0.54

MutPred

0.45

Gain of catalytic residue at G14 (P = 0);Gain of catalytic residue at G14 (P = 0);Gain of catalytic residue at G14 (P = 0);

MVP

0.84

MPC

0.24

ClinPred

0.30

GERP RS

1.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.29

gMVP

0.85

Mutation Taster

=57/43

polymorphism

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over