13-113118772-T-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP3_StrongPP5_Moderate

The NM_019616.4(F7):ā€‹c.1099T>Gā€‹(p.Cys367Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,460,948 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 Pathogenic (ā˜…).

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 0.0000034 ( 0 hom. )

Consequence

F7
NM_019616.4 missense

Scores

14
2
3

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 6.04
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_019616.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.99
PP5
Variant 13-113118772-T-G is Pathogenic according to our data. Variant chr13-113118772-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 12085.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
F7NM_019616.4 linkuse as main transcriptc.1099T>G p.Cys367Gly missense_variant 8/8 ENST00000346342.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
F7ENST00000346342.8 linkuse as main transcriptc.1099T>G p.Cys367Gly missense_variant 8/81 NM_019616.4 P2P08709-2
F7ENST00000375581.3 linkuse as main transcriptc.1165T>G p.Cys389Gly missense_variant 9/91 A2P08709-1
F7ENST00000541084.5 linkuse as main transcriptc.913T>G p.Cys305Gly missense_variant 6/62

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.0000401
AC:
10
AN:
249480
Hom.:
0
AF XY:
0.0000369
AC XY:
5
AN XY:
135414
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000545
Gnomad SAS 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:
0.00000342
AC:
5
AN:
1460948
Hom.:
0
Cov.:
33
AF XY:
0.00000275
AC XY:
2
AN XY:
726772
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000126
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
ExAC
AF:
0.0000412
AC:
5

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Factor VII deficiency Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMOct 01, 2000- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.96
BayesDel_addAF
Pathogenic
0.23
D
BayesDel_noAF
Pathogenic
0.42
CADD
Pathogenic
26
DANN
Benign
0.97
DEOGEN2
Pathogenic
0.96
.;.;D
Eigen
Pathogenic
0.74
Eigen_PC
Uncertain
0.55
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Benign
0.64
T;T;T
M_CAP
Pathogenic
0.77
D
MetaRNN
Pathogenic
0.99
D;D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
3.6
.;.;H
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.61
T
PROVEAN
Pathogenic
-12
.;D;D
REVEL
Pathogenic
0.93
Sift
Pathogenic
0.0
.;D;D
Sift4G
Pathogenic
0.0
D;D;D
Polyphen
1.0
.;D;D
Vest4
0.95
MutPred
0.89
.;.;Gain of catalytic residue at S393 (P = 0);
MVP
0.98
MPC
0.83
ClinPred
1.0
D
GERP RS
4.1
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.

Other links and lift over

dbSNP: rs121964934; hg19: chr13-113773086; API