rs121918482

Positions:

• chr11-46728157-G-A
• chr11-46728157-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PS1_Moderate PM1 PP3_Strong PP5

The ENST00000311907.10(F2):​c.1292G>A​(p.Arg431His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000055 in 1,455,532 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: F2 ENST00000311907.10 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.71

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PS1: Transcript ENST00000311907.10 (F2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in ENST00000311907.10
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.976
• PP5: Variant 11-46728157-G-A is Pathogenic according to our data. Variant chr11-46728157-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 13308.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-46728157-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
F2	NM_000506.5	c.1292G>A	p.Arg431His	missense_variant	10/14	ENST00000311907.10	NP_000497.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F2	ENST00000311907.10	c.1292G>A	p.Arg431His	missense_variant	10/14	1	NM_000506.5	ENSP00000308541	P1
F2	ENST00000530231.5	c.1292G>A	p.Arg431His	missense_variant	10/14	5		ENSP00000433907

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000550 AC: 8 AN: 1455532 Hom.: 0 Cov.: 32 AF XY: 0.00000691 AC XY: 5 AN XY: 723178

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000228

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000119

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000451

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

DYSPROTHROMBINEMIA PROTHROMBIN HIMI-II Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 1992

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.66	D;D
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D;T
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	0.72	D
MutationAssessor	Benign	1.4	L;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Pathogenic	0.91
Sift4G	Uncertain	0.0060	D;D
Polyphen		1.0	D;.
Vest4		0.73
MutPred		0.91		Loss of MoRF binding (P = 0.0262);Loss of MoRF binding (P = 0.0262);
MVP		1.0
MPC		1.7
ClinPred		0.99	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.97
gMVP		0.79

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: rs121918482; hg19: chr11-46749707; COSMIC: COSV61314835; COSMIC: COSV61314835;