NM_019616.4:c.783_799delGCGGGTGGCGCAGGTCA

Variant names:

• chr13-113118455-GGCGGGTGGCGCAGGTCA-G
• rs786205091
• NM_019616.4:c.783_799delGCGGGTGGCGCAGGTCA

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1 PP5

The NM_019616.4(F7):​c.783_799delGCGGGTGGCGCAGGTCA​(p.Arg262HisfsTer27) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: F7 NM_019616.4 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 6.06
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• congenital factor VII deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Orphanet, Ambry Genetics
• factor VII deficiency

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 40 pathogenic variants in the truncated region.
• PP5: Variant 13-113118455-GGCGGGTGGCGCAGGTCA-G is Pathogenic according to our data. Variant chr13-113118455-GGCGGGTGGCGCAGGTCA-G is described in ClinVar as Pathogenic. ClinVar VariationId is 12077.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F7	NM_019616.4	c.783_799delGCGGGTGGCGCAGGTCA	p.Arg262HisfsTer27	frameshift_variant	Exon 8 of 8	ENST00000346342.8	NP_062562.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F7	ENST00000346342.8	c.783_799delGCGGGTGGCGCAGGTCA	p.Arg262HisfsTer27	frameshift_variant	Exon 8 of 8	1	NM_019616.4	ENSP00000329546.4
F7	ENST00000375581.3	c.849_865delGCGGGTGGCGCAGGTCA	p.Arg284HisfsTer27	frameshift_variant	Exon 9 of 9	1		ENSP00000364731.3
F7	ENST00000541084.5	c.597_613delGCGGGTGGCGCAGGTCA	p.Arg200HisfsTer27	frameshift_variant	Exon 6 of 6	2		ENSP00000442051.2

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Factor VII deficiency Pathogenic:1

Jul 01, 1994

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Congenital factor VII deficiency Pathogenic:1

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ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.1
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs786205091; hg19: chr13-113772769;