chr11-46723453-C-G

Position:

• chr11-46723453-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_000506.5(F2):​c.494C>G​(p.Thr165Arg) 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. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T165M) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: F2 NM_000506.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.246

Genes affected

F2 (HGNC:3535): (coagulation factor II, thrombin) This gene encodes the prothrombin protein (also known as coagulation factor II). This protein is proteolytically cleaved in multiple steps to form the activated serine protease thrombin. The activated thrombin enzyme plays an important role in thrombosis and hemostasis by converting fibrinogen to fibrin during blood clot formation, by stimulating platelet aggregation, and by activating additional coagulation factors. Thrombin also plays a role in cell proliferation, tissue repair, and angiogenesis as well as maintaining vascular integrity during development and postnatal life. Peptides derived from the C-terminus of this protein have antimicrobial activity against E. coli and P. aeruginosa. Mutations in this gene lead to various forms of thrombosis and dysprothrombinemia. Rapid increases in cytokine levels following coronavirus infections can dysregulate the coagulation cascade and produce thrombosis, compromised blood supply, and organ failure. [provided by RefSeq, May 2020]

F2 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a peptide Activation peptide fragment 1 (size 154) in uniprot entity THRB_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_000506.5
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25667053).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
F2	NM_000506.5	c.494C>G	p.Thr165Arg	missense_variant	6/14	ENST00000311907.10	NP_000497.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F2	ENST00000311907.10	c.494C>G	p.Thr165Arg	missense_variant	6/14	1	NM_000506.5	ENSP00000308541.5
F2	ENST00000530231.5	c.494C>G	p.Thr165Arg	missense_variant	6/14	5		ENSP00000433907.1
F2	ENST00000442468.1	c.464C>G	p.Thr155Arg	missense_variant	6/8	3		ENSP00000387413.1
F2	ENST00000490274.1	n.274C>G		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.086	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	2.8
DANN	Benign	0.91
DEOGEN2	Benign	0.045	T;T;T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.54	T;T;T
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.26	T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.87	L;.;.
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.17	N;N;N
REVEL	Benign	0.11
Sift	Benign	0.14	.;.;T
Sift4G	Benign	0.53	T;T;T
Polyphen		0.52	P;.;.
Vest4		0.17
MutPred		0.50		Loss of glycosylation at T165 (P = 0.0669);Loss of glycosylation at T165 (P = 0.0669);.;
MVP		0.61
MPC		0.89
ClinPred		0.16	T
GERP RS		3.0
Varity_R		0.32
gMVP		0.72

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

Other links and lift over

dbSNP: rs5896; hg19: chr11-46745003;