chr13-113118590-T-C

Variant names:

• chr13-113118590-T-C
• rs387906508
• NM_019616.4:c.917T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP2 PP5

The NM_019616.4(F7):​c.917T>C​(p.Phe306Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: F7 NM_019616.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.01
• Publications: 5 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 6 ACMG points.

• PM1: In a disulfide_bond (size 127) in uniprot entity FA7_HUMAN there are 19 pathogenic changes around while only 3 benign (86%) in NM_019616.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 39 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. Gene score misZ: 0.31991 (below the threshold of 3.09). Trascript score misZ: 0.36088 (below the threshold of 3.09). GenCC associations: The gene is linked to congenital factor VII deficiency, factor VII deficiency.
• PP5: Variant 13-113118590-T-C is Pathogenic according to our data. Variant chr13-113118590-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 12090.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.917T>C	p.Phe306Ser	missense_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.917T>C	p.Phe306Ser	missense_variant	Exon 8 of 8	1	NM_019616.4	ENSP00000329546.4
F7	ENST00000375581.3	c.983T>C	p.Phe328Ser	missense_variant	Exon 9 of 9	1		ENSP00000364731.3
F7	ENST00000541084.5	c.731T>C	p.Phe244Ser	missense_variant	Exon 6 of 6	2		ENSP00000442051.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

Alfa AF: 0.000998 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Factor VII deficiency Pathogenic:1

Nov 29, 1996

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	.;.;D
Eigen	Benign	0.081
Eigen_PC	Benign	0.013
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.76	T;T;T
M_CAP	Uncertain	0.28	D
MetaRNN	Uncertain	0.72	D;D;D
MetaSVM	Uncertain	-0.021	T
MutationAssessor	Benign	0.87	.;.;L
PhyloP100		4.0
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-5.8	.;D;D
REVEL	Uncertain	0.54
Sift	Benign	0.051	.;T;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.44
MutPred		0.55		.;.;Gain of catalytic residue at L323 (P = 0);
MVP		0.93
MPC		1.0
ClinPred		0.98	D
GERP RS		4.4
Varity_R		0.94
gMVP		0.90
Mutation Taster		=7/93	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs387906508; hg19: chr13-113772904;