1-94536036-T-A

Position:

• chr1-94536036-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001993.5(F3):​c.341A>T​(p.Asn114Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: F3 NM_001993.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.383

Genes affected

F3 (HGNC:3541): (coagulation factor III, tissue factor) This gene encodes coagulation factor III which is a cell surface glycoprotein. This factor enables cells to initiate the blood coagulation cascades, and it functions as the high-affinity receptor for the coagulation factor VII. The resulting complex provides a catalytic event that is responsible for initiation of the coagulation protease cascades by specific limited proteolysis. Unlike the other cofactors of these protease cascades, which circulate as nonfunctional precursors, this factor is a potent initiator that is fully functional when expressed on cell surfaces, for example, on monocytes. There are 3 distinct domains of this factor: extracellular, transmembrane, and cytoplasmic. Platelets and monocytes have been shown to express this coagulation factor under procoagulatory and proinflammatory stimuli, and a major role in HIV-associated coagulopathy has been described. Platelet-dependent monocyte expression of coagulation factor III has been described to be associated with Coronavirus Disease 2019 (COVID-19) severity and mortality. This protein is the only one in the coagulation pathway for which a congenital deficiency has not been described. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Aug 2020]

F3 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19017276).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
F3	NM_001993.5	c.341A>T	p.Asn114Ile	missense_variant	3/6	ENST00000334047.12	NP_001984.1
F3	NM_001178096.2	c.341A>T	p.Asn114Ile	missense_variant	3/5		NP_001171567.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F3	ENST00000334047.12	c.341A>T	p.Asn114Ile	missense_variant	3/6	1	NM_001993.5	ENSP00000334145.7
F3	ENST00000370207.4	c.341A>T	p.Asn114Ile	missense_variant	3/5	1		ENSP00000359226.4
F3	ENST00000478217.5	n.129A>T		non_coding_transcript_exon_variant	1/2	3
F3	ENST00000480356.1	n.959A>T		non_coding_transcript_exon_variant	4/5	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461872 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 12, 2024

The c.341A>T (p.N114I) alteration is located in exon 3 (coding exon 3) of the F3 gene. This alteration results from a A to T substitution at nucleotide position 341, causing the asparagine (N) at amino acid position 114 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	7.1
DANN	Benign	0.97
DEOGEN2	Benign	0.35	T;.
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.41	T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.19	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.1	M;M
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-2.4	N;N
REVEL	Benign	0.14
Sift	Benign	0.044	D;T
Sift4G	Uncertain	0.042	D;T
Polyphen		0.74	P;P
Vest4		0.10
MutPred		0.47		Loss of catalytic residue at N114 (P = 0.0042);Loss of catalytic residue at N114 (P = 0.0042);
MVP		0.77
MPC		0.40
ClinPred		0.16	T
GERP RS		2.1
Varity_R		0.50
gMVP		0.67

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-95001592;