chr13-113106850-G-A

Variant names:

• chr13-113106850-G-A
• rs773842154
• ENST00000375581.3:c.70G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_000131.5(F7):​c.70G>A​(p.Val24Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000345 in 1,449,678 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 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. V24F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: F7 NM_000131.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0360
• 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), Ambry Genetics, Orphanet, Laboratory for Molecular Medicine
• factor VII deficiency

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• 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: 0.24236 (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=0.06969145).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000131.5. 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.64+945G>A		intron	N/A	NP_062562.1	P08709-2
	F7	NM_000131.5		c.70G>A	p.Val24Ile	missense	Exon 2 of 9	NP_000122.1
	F7	NM_001267554.2		c.64+945G>A		intron	N/A	NP_001254483.1	F5H8B0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F7	ENST00000375581.3	TSL:1	c.70G>A	p.Val24Ile	missense	Exon 2 of 9	ENSP00000364731.3	P08709-1
	F7	ENST00000346342.8	TSL:1 MANE Select	c.64+945G>A		intron	N/A	ENSP00000329546.4	P08709-2
	F7	ENST00000891251.1		c.70G>A	p.Val24Ile	missense	Exon 2 of 10	ENSP00000561310.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000131 AC: 3 AN: 229552 AF XY: 0.00000802

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000294

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000345 AC: 5 AN: 1449678 Hom.: 0 Cov.: 31 AF XY: 0.00000278 AC XY: 2 AN XY: 720100

African (AFR) AF: 0.00 AC: 0 AN: 33308

American (AMR) AF: 0.00 AC: 0 AN: 43552

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25860

East Asian (EAS) AF: 0.00 AC: 0 AN: 39382

South Asian (SAS) AF: 0.00 AC: 0 AN: 84486

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51276

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00000452 AC: 5 AN: 1106172

Other (OTH) AF: 0.00 AC: 0 AN: 59886

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000832 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	4.3
DANN	Benign	0.78
DEOGEN2	Benign	0.21	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.00046	N
LIST_S2	Benign	0.25	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.070	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.036
PrimateAI	Benign	0.43	T
PROVEAN	Benign	0.050	N
REVEL	Benign	0.079
Sift	Benign	0.18	T
Sift4G	Benign	0.38	T
Polyphen		0.084	B
Vest4		0.18
MutPred		0.29		Gain of catalytic residue at L19 (P = 0)
MVP		0.56
MPC		0.18
ClinPred		0.031	T
GERP RS		-1.0
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.2
Varity_R		0.039
gMVP		0.50
Mutation Taster		=97/3	polymorphism

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: rs773842154; hg19: chr13-113761164;