13-113115754-C-T

Variant names:

• chr13-113115754-C-T
• rs6042
• NM_019616.4:c.459C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_019616.4(F7):​c.459C>T​(p.His153His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.126 in 1,613,076 control chromosomes in the GnomAD database, including 14,626 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1330 hom., cov: 33)
  • Exomes 𝑓: 0.13 (13296 hom.)
• Consequence: F7 NM_019616.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.13

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

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 13-113115754-C-T is Benign according to our data. Variant chr13-113115754-C-T is described in ClinVar as [Benign]. Clinvar id is 255218.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-113115754-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.13 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.264 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F7	NM_019616.4	c.459C>T	p.His153His	synonymous_variant	Exon 5 of 8	ENST00000346342.8	NP_062562.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F7	ENST00000346342.8	c.459C>T	p.His153His	synonymous_variant	Exon 5 of 8	1	NM_019616.4	ENSP00000329546.4

Frequencies

GnomAD3 genomes AF: 0.127 AC: 19248 AN: 152142 Hom.: 1328 Cov.: 33

Gnomad AFR AF: 0.134

Gnomad AMI AF: 0.174

Gnomad AMR AF: 0.122

Gnomad ASJ AF: 0.207

Gnomad EAS AF: 0.0472

Gnomad SAS AF: 0.276

Gnomad FIN AF: 0.0765

Gnomad MID AF: 0.207

Gnomad NFE AF: 0.120

Gnomad OTH AF: 0.144

GnomAD2 exomes AF: 0.137 AC: 34334 AN: 250174 AF XY: 0.146

Gnomad AFR exome AF: 0.136

Gnomad AMR exome AF: 0.115

Gnomad ASJ exome AF: 0.195

Gnomad EAS exome AF: 0.0502

Gnomad FIN exome AF: 0.0749

Gnomad NFE exome AF: 0.126

Gnomad OTH exome AF: 0.142

GnomAD4 exome AF: 0.126 AC: 183916 AN: 1460816 Hom.: 13296 Cov.: 33 AF XY: 0.132 AC XY: 95567 AN XY: 726700

Gnomad4 AFR exome AF: 0.138 AC: 4627 AN: 33478

Gnomad4 AMR exome AF: 0.118 AC: 5269 AN: 44712

Gnomad4 ASJ exome AF: 0.195 AC: 5104 AN: 26136

Gnomad4 EAS exome AF: 0.0580 AC: 2304 AN: 39700

Gnomad4 SAS exome AF: 0.278 AC: 23941 AN: 86248

Gnomad4 FIN exome AF: 0.0786 AC: 4125 AN: 52456

Gnomad4 NFE exome AF: 0.116 AC: 129202 AN: 1111942

Gnomad4 Remaining exome AF: 0.134 AC: 8070 AN: 60376

GnomAD4 genome AF: 0.126 AC: 19256 AN: 152260 Hom.: 1330 Cov.: 33 AF XY: 0.126 AC XY: 9374 AN XY: 74432

Gnomad4 AFR AF: 0.134 AC: 0.134314 AN: 0.134314

Gnomad4 AMR AF: 0.122 AC: 0.122304 AN: 0.122304

Gnomad4 ASJ AF: 0.207 AC: 0.207373 AN: 0.207373

Gnomad4 EAS AF: 0.0473 AC: 0.0472608 AN: 0.0472608

Gnomad4 SAS AF: 0.276 AC: 0.276141 AN: 0.276141

Gnomad4 FIN AF: 0.0765 AC: 0.0765094 AN: 0.0765094

Gnomad4 NFE AF: 0.120 AC: 0.120222 AN: 0.120222

Gnomad4 OTH AF: 0.143 AC: 0.142857 AN: 0.142857

Alfa AF: 0.128 Hom.: 2567

Bravo AF: 0.129

Asia WGS AF: 0.159 AC: 552 AN: 3478

EpiCase AF: 0.136

EpiControl AF: 0.137

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

Nov 20, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Factor VII deficiency Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.3
DANN	Benign	0.63
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs6042; hg19: chr13-113770068; COSMIC: COSV60645205; COSMIC: COSV60645205;