13-113118845-G-T

Variant names:

• chr13-113118845-G-T
• rs6046
• NM_019616.4:c.1172G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 5P and 2B. PM1 PM2 PP2 BP4_Moderate

The NM_019616.4(F7):​c.1172G>T​(p.Arg391Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R391Q) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: F7 NM_019616.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0900
• Publications: 111 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: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• factor VII deficiency

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 1 uncertain 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2199825).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019616.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F7	NM_019616.4	MANE Select	c.1172G>T	p.Arg391Leu	missense	Exon 8 of 8	NP_062562.1	P08709-2
	F7	NM_000131.5		c.1238G>T	p.Arg413Leu	missense	Exon 9 of 9	NP_000122.1
	F7	NM_001267554.2		c.986G>T	p.Arg329Leu	missense	Exon 6 of 6	NP_001254483.1	F5H8B0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F7	ENST00000346342.8	TSL:1 MANE Select	c.1172G>T	p.Arg391Leu	missense	Exon 8 of 8	ENSP00000329546.4	P08709-2
	F7	ENST00000375581.3	TSL:1	c.1238G>T	p.Arg413Leu	missense	Exon 9 of 9	ENSP00000364731.3	P08709-1
	F7	ENST00000891255.1		c.1385G>T	p.Arg462Leu	missense	Exon 9 of 9	ENSP00000561314.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	0.0088	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Uncertain	0.77	D
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.85	T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	1.1	L
PhyloP100		-0.090
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-4.1	D
REVEL	Uncertain	0.39
Sift	Benign	0.037	D
Sift4G	Uncertain	0.043	D
Polyphen		0.87	P
Vest4		0.42
MutPred		0.55		Gain of catalytic residue at Y412 (P = 0)
MVP		0.66
MPC		0.43
ClinPred		0.68	D
GERP RS		-4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.45
gMVP		0.70
Mutation Taster		=42/58	disease causing

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: rs6046; hg19: chr13-113773159;