Variant rs121964927 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong

The ENST00000346342.8(F7):c.1043G>A(p.Cys348Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,460,754 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. C348F) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

F7
ENST00000346342.8 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.47

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in ENST00000346342.8

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr13-113118716-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 265135.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.985

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
F7	NM_019616.4 linkuse as main transcript	c.1043G>A	p.Cys348Tyr	missense_variant	8/8	ENST00000346342.8	NP_062562.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F7	ENST00000346342.8 linkuse as main transcript	c.1043G>A	p.Cys348Tyr	missense_variant	8/8	1	NM_019616.4	ENSP00000329546	P2	P08709-2
F7	ENST00000375581.3 linkuse as main transcript	c.1109G>A	p.Cys370Tyr	missense_variant	9/9	1		ENSP00000364731	A2	P08709-1
F7	ENST00000541084.5 linkuse as main transcript	c.857G>A	p.Cys286Tyr	missense_variant	6/6	2		ENSP00000442051

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000804

AC:

AN:

248908

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135286

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

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:

0.00000893

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1460754

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726670

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.43

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.96

.;.;D

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.81

T;T;T

M_CAP

Pathogenic

0.40

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.8

.;.;H

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.76

PROVEAN

Pathogenic

-8.6

.;D;D

REVEL

Pathogenic

0.90

Sift

Pathogenic

0.0

.;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

.;D;D

Vest4

0.94

MutPred

0.82

.;.;Gain of catalytic residue at L365 (P = 0.0086);

MVP

0.98

MPC

0.98

ClinPred

1.0

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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.

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