1-94540363-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001993.5(F3):ā€‹c.106A>Gā€‹(p.Thr36Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00129 in 1,610,278 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (ā˜…ā˜…). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: š‘“ 0.0070 ( 13 hom., cov: 33)
Exomes š‘“: 0.00069 ( 12 hom. )

Consequence

F3
NM_001993.5 missense

Scores

18

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.961
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0027884245).
BP6
Variant 1-94540363-T-C is Benign according to our data. Variant chr1-94540363-T-C is described in ClinVar as [Benign]. Clinvar id is 717135.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00701 (1068/152356) while in subpopulation AFR AF= 0.0247 (1027/41570). AF 95% confidence interval is 0.0235. There are 13 homozygotes in gnomad4. There are 495 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 13 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
F3NM_001993.5 linkuse as main transcriptc.106A>G p.Thr36Ala missense_variant 2/6 ENST00000334047.12 NP_001984.1 P13726-1
F3NM_001178096.2 linkuse as main transcriptc.106A>G p.Thr36Ala missense_variant 2/5 NP_001171567.1 P13726-2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
F3ENST00000334047.12 linkuse as main transcriptc.106A>G p.Thr36Ala missense_variant 2/61 NM_001993.5 ENSP00000334145.7 P13726-1
F3ENST00000370207.4 linkuse as main transcriptc.106A>G p.Thr36Ala missense_variant 2/51 ENSP00000359226.4 P13726-2
F3ENST00000480356.1 linkuse as main transcriptn.724A>G non_coding_transcript_exon_variant 3/55

Frequencies

GnomAD3 genomes
AF:
0.00700
AC:
1066
AN:
152238
Hom.:
13
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0247
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00196
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00382
GnomAD3 exomes
AF:
0.00180
AC:
452
AN:
250872
Hom.:
7
AF XY:
0.00130
AC XY:
176
AN XY:
135652
show subpopulations
Gnomad AFR exome
AF:
0.0260
Gnomad AMR exome
AF:
0.000786
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000491
GnomAD4 exome
AF:
0.000690
AC:
1006
AN:
1457922
Hom.:
12
Cov.:
28
AF XY:
0.000600
AC XY:
435
AN XY:
725588
show subpopulations
Gnomad4 AFR exome
AF:
0.0270
Gnomad4 AMR exome
AF:
0.000852
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000271
Gnomad4 OTH exome
AF:
0.00101
GnomAD4 genome
AF:
0.00701
AC:
1068
AN:
152356
Hom.:
13
Cov.:
33
AF XY:
0.00664
AC XY:
495
AN XY:
74504
show subpopulations
Gnomad4 AFR
AF:
0.0247
Gnomad4 AMR
AF:
0.00196
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00378
Alfa
AF:
0.00117
Hom.:
4
Bravo
AF:
0.00788
ESP6500AA
AF:
0.0256
AC:
113
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.00239
AC:
290
Asia WGS
AF:
0.000577
AC:
2
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJun 06, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.065
BayesDel_addAF
Benign
-0.63
T
BayesDel_noAF
Benign
-0.66
CADD
Benign
0.30
DANN
Benign
0.77
DEOGEN2
Benign
0.097
T;.
Eigen
Benign
-1.5
Eigen_PC
Benign
-1.5
FATHMM_MKL
Benign
0.049
N
LIST_S2
Benign
0.41
T;T
MetaRNN
Benign
0.0028
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.20
N;N
PrimateAI
Benign
0.40
T
PROVEAN
Benign
-0.73
N;N
REVEL
Benign
0.062
Sift
Benign
0.85
T;T
Sift4G
Benign
0.81
T;T
Polyphen
0.0
B;B
Vest4
0.052
MVP
0.51
MPC
0.27
ClinPred
0.0016
T
GERP RS
-4.6
Varity_R
0.13
gMVP
0.40

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs3917604; hg19: chr1-95005919; API