chr13-113118831-T-G

Position:

chr13-113118831-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP5_Moderate

The ENST00000346342.8(F7):c.1158T>G(p.His386Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000806 in 1,612,736 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

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

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

F7
ENST00000346342.8 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: -1.72

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 Likely_pathogenic. Variant got 6 ACMG points.

PM1

In a disulfide_bond (size 19) in uniprot entity FA7_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in ENST00000346342.8

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 13-113118831-T-G is Pathogenic according to our data. Variant chr13-113118831-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 12088.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
F7	NM_019616.4 linkuse as main transcript	c.1158T>G	p.His386Gln	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.1158T>G	p.His386Gln	missense_variant	8/8	1	NM_019616.4	ENSP00000329546	P2	P08709-2
F7	ENST00000375581.3 linkuse as main transcript	c.1224T>G	p.His408Gln	missense_variant	9/9	1		ENSP00000364731	A2	P08709-1
F7	ENST00000541084.5 linkuse as main transcript	c.972T>G	p.His324Gln	missense_variant	6/6	2		ENSP00000442051

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152098

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000242

AC:

AN:

247436

Hom.:

AF XY:

0.0000297

AC XY:

AN XY:

134780

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000331

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:

0.00000753

AC:

AN:

1460520

Hom.:

Cov.:

AF XY:

0.00000826

AC XY:

AN XY:

726548

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000277

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

AF:

0.0000131

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000387

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.0000248

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Factor VII deficiency

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2002	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 25, 2020	The p.His408Gln variant in F7 has been reported in 3 homozygous and 3 compound heterozygous individuals with factor VII deficiency and segregated with disease in 2 affected individuals from 2 families ( Katsumi 2000 PMID: 10739380, Shen 2001 PMID: 11260055, Jin 2011 PMID: 21287501, Li 2013 PMID: 23358202, Jin 2015 PMID: 25863091, Wang 2018 PMID: 30208845). It has also been identified in 0.033% (6/18114) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies provide some evidence that this variant impacts protein function (Katsumi 2000 PMID: 10739380); however, these types of assays may not accurately represent biological function. Another variant at the same codon (p.His408Arg) has been identified in individuals with factor VII deficiency, suggesting that change at this position may not be tolerated. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive factor VII deficiency. ACMG/AMP criteria applied: PM3_Strong, PM5, PP1_Moderate, PS3_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.86

BayesDel_addAF

Uncertain

0.068

BayesDel_noAF

Pathogenic

0.17

CADD

Benign

2.6

DANN

Benign

0.90

DEOGEN2

Pathogenic

0.87

.;.;D

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.067

LIST_S2

Uncertain

0.90

D;D;D

M_CAP

Uncertain

0.15

MetaRNN

Uncertain

0.72

D;D;D

MetaSVM

Uncertain

0.26

MutationAssessor

Benign

0.28

.;.;N

MutationTaster

Benign

0.86

D;D;D

PrimateAI

Uncertain

0.49

PROVEAN

Pathogenic

-5.5

.;D;D

REVEL

Uncertain

0.50

Sift

Benign

0.049

.;D;D

Sift4G

Uncertain

0.046

D;T;T

Polyphen

1.0

.;D;D

Vest4

0.77

MutPred

0.78

.;.;Gain of catalytic residue at S404 (P = 0);

MVP

0.84

MPC

0.74

ClinPred

0.41

GERP RS

-5.6

Varity_R

0.95

gMVP

0.92

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