rs755377592

Positions:

chr13-113118892-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5

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 (no stars).

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 no assertion criteria provided P:2

Conservation

PhyloP100: 6.70

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 Likely_pathogenic. Variant got 9 ACMG points.

PM1

In a disulfide_bond (size 28) in uniprot entity FA7_HUMAN there are 13 pathogenic changes around while only 0 benign (100%) in NM_019616.4

PM2

Very rare variant in population databases, with high coverage;

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 id is 374352.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
F7	NM_019616.4 linkuse as main transcript	c.1219G>A	p.Ala407Thr	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.1219G>A	p.Ala407Thr	missense_variant	8/8	1	NM_019616.4	ENSP00000329546.4	P08709-2
F7	ENST00000375581.3 linkuse as main transcript	c.1285G>A	p.Ala429Thr	missense_variant	9/9	1		ENSP00000364731.3	P08709-1
F7	ENST00000541084.5 linkuse as main transcript	c.1033G>A	p.Ala345Thr	missense_variant	6/6	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

GnomAD3 exomes

AF:

0.0000765

AC:

AN:

248338

Hom.:

AF XY:

0.0000740

AC XY:

AN XY:

135056

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 SAS 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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000358

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000126

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152200

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000577

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Factor VII deficiency

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Baylor Genetics

Jun 30, 2014

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

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 26, 2023

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

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

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

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