rs36209567

chr13-113118668-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP5

The NM_019616.4(F7):c.995C>T(p.Ala332Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000401 in 1,612,734 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00036 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00040 (0 hom.)
• Consequence: F7 NM_019616.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:13 U:1
• Conservation: PhyloP100: 7.22

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a domain Peptidase S1 (size 239) in uniprot entity FA7_HUMAN there are 97 pathogenic changes around while only 10 benign (91%) in NM_019616.4
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-113118668-C-T is Pathogenic according to our data. Variant chr13-113118668-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 12076.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=8, Pathogenic=4, Uncertain_significance=1}. Variant chr13-113118668-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
F7	NM_019616.4	c.995C>T	p.Ala332Val	missense_variant	8/8	ENST00000346342.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F7	ENST00000346342.8	c.995C>T	p.Ala332Val	missense_variant	8/8	1	NM_019616.4	P2
F7	ENST00000375581.3	c.1061C>T	p.Ala354Val	missense_variant	9/9	1		A2
F7	ENST00000541084.5	c.809C>T	p.Ala270Val	missense_variant	6/6	2

Frequencies

GnomAD3 genomes AF: 0.000362 AC: 55 AN: 152064 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000559

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000563 AC: 140 AN: 248594 Hom.: 0 AF XY: 0.000547 AC XY: 74 AN XY: 135182

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000871

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000933

Gnomad NFE exome AF: 0.00104

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000405 AC: 591 AN: 1460554 Hom.: 0 Cov.: 33 AF XY: 0.000380 AC XY: 276 AN XY: 726586

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000823

Gnomad4 NFE exome AF: 0.000474

Gnomad4 OTH exome AF: 0.000248

GnomAD4 genome AF: 0.000361 AC: 55 AN: 152180 Hom.: 0 Cov.: 33 AF XY: 0.000336 AC XY: 25 AN XY: 74404

Gnomad4 AFR AF: 0.0000723

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.000559

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000331 Hom.: 0

Bravo AF: 0.000257

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000726 AC: 88

EpiCase AF: 0.000327

EpiControl AF: 0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:13 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 01, 2021	This sequence change replaces alanine with valine at codon 354 of the F7 protein (p.Ala354Val). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs36209567, ExAC 0.1%). This missense change has been observed in individuals with factor VII deficiency (PMID: 7919338, 7981691, 10862079, 15735798). It has also been observed to segregate with disease in related individuals. This variant is also known as Ala294Val. ClinVar contains an entry for this variant (Variation ID: 12076). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	F7: PS4, PM2, PS3:Moderate, PP4 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 14, 2022	PP5, PM3, PS3 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Feb 25, 2021	PS3, PM3_Supporting, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 08, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24533960, 31064749, 22180436, 7981691, 30431218, 31980526, 31589614, 29431110, 29618153, 33406812, 15735798) -

Factor VII deficiency Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2000	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 15, 2018	The F7 c.1061C>T (p.Ala354Val) missense variant, previously known as p.Ala294Val, has been reported in more than seven studies in which it is found in a total of more than 97 alleles in individuals with factor VII deficiency, including 10 homozygotes and four compound heterozygotes (Bernardi et al. 1994; Wulff et al. 2000; Fromovich-Amit et al. 2004; Mariani et al. 2005; Marty et al. 2008; Branchini et al. 2012; Pavlova et al. 2015). Of note, this variant is also described in cis with a second variant, c.11128delC, in an additional 111 alleles in affected individuals, including 26 individuals homozygous for both variants. The p.Ala354Val variant was absent from 20 controls, but is reported at a frequency of 0.00128 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional analysis of FVII activity in the plasma of a homozygous individual carrying this variant and the second variant, c.11128delC, showed drastically reduced activity. In vivo studies of the p.Ala354Val variant identified decreased activation of FX by variant FVII protein; however, functional studies showed discordant results when evaluating alterations in the variant protein's interaction with activators and cofactors (Toso et al. 2002; Fromovich-Amit et al. 2004; Branchini et al. 2012). Based on the evidence, the p.Ala354Val variant is classified as pathogenic for factor VII deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Sep 11, 2019	This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PM1,PM2,PP3,PP5. -
Pathogenic, criteria provided, single submitter	research	NIHR Bioresource Rare Diseases, University of Cambridge	Feb 01, 2019	- -

Congenital factor VII deficiency Pathogenic:2 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Oct 07, 2022	The F7 c.995C>T variant is classified as LIKELY PATHOGENIC (PM2_Supporting, PM1, PM3, PP4) The F7 c.995C>T variant is a single nucleotide substitution in exon 8/8 of the F7 gene, which is predicted to change the alanine at position 332 in the protein to valine. This variant is in dbSNP (rs36209567) and is present in population databases at extremely low frequency (0.00002%, AR) (PM2_Supporting). The variant is in a functional domain (PM1). This variant has been reported as homozygous and compound heterozygous and was detected in trans in this patient with a likely pathogenic variant (PM3). The patient’s phenotype is highly specific for a disease with a single genetic aetiology (biochemical functional assay show low FVII activity) (PP4). -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 10, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	-	- -

Congenital factor VII deficiency;C1832662:Myocardial infarction, susceptibility to Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 27, 2022

- -

Abnormal bleeding Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

NIHR Bioresource Rare Diseases, University of Cambridge

Feb 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.17
Cadd	Benign	23
Dann	Uncertain	1.0
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.096
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Uncertain	0.49	T;T;T
MetaSVM	Uncertain	0.11	D
MutationTaster	Benign	0.000047	A;A;A
PrimateAI	Uncertain	0.50	T
REVEL	Uncertain	0.34
Sift4G	Uncertain	0.010	D;D;D
Polyphen		0.98, 0.98	.;D;D
Vest4		0.21
MVP		0.90
MPC		0.72
ClinPred		0.17	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.73
gMVP		0.84

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

Other links and lift over

dbSNP: rs36209567; hg19: chr13-113772982;