rs757953549

Positions:

• chr1-169542872-G-A
• chr1-169542872-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The ENST00000367797.9(F5):​c.2218C>T​(p.Arg740Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000226 in 1,461,830 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R740R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: F5 ENST00000367797.9 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 2.36

Genes affected

F5 (HGNC:3542): (coagulation factor V) This gene encodes an essential cofactor of the blood coagulation cascade. This factor circulates in plasma, and is converted to the active form by the release of the activation peptide by thrombin during coagulation. This generates a heavy chain and a light chain which are held together by calcium ions. The activated protein is a cofactor that participates with activated coagulation factor X to activate prothrombin to thrombin. Defects in this gene result in either an autosomal recessive hemorrhagic diathesis or an autosomal dominant form of thrombophilia, which is known as activated protein C resistance. [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 1-169542872-G-A is Pathogenic according to our data. Variant chr1-169542872-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 293622.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-169542872-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
F5	NM_000130.5	c.2218C>T	p.Arg740Ter	stop_gained	13/25	ENST00000367797.9	NP_000121.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F5	ENST00000367797.9	c.2218C>T	p.Arg740Ter	stop_gained	13/25	1	NM_000130.5	ENSP00000356771	P2
F5	ENST00000367796.3	c.2233C>T	p.Arg745Ter	stop_gained	13/25	5		ENSP00000356770	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000226 AC: 33 AN: 1461830 Hom.: 0 Cov.: 42 AF XY: 0.0000234 AC XY: 17 AN XY: 727218

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000252

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital factor V deficiency Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 20, 2023

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 293622). This premature translational stop signal has been observed in individual(s) with clinical features of autosomal recessive factor V deficiency (PMID: 9694743, 31399523, 34575869). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg740*) in the F5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in F5 are known to be pathogenic (PMID: 30924984). -

Factor V deficiency Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

The F5 c.2218C>T (p.Arg740Ter) variant, also referred to as c.2308C>T (p.Arg712Ter), is a stop-gained variant that is predicted to result in premature termination of the protein. The p.Arg740Ter variant has been reported in three studies in which it is found in a compound heterozygous state in three individuals with factor V deficiency (Lunghi et al. 1998; Montefusco et al. 2003; Segers et al. 2012). Two of these individuals also carried the factor V Leiden variant and were classified as having pseudo-homozygous activated protein C (APC) resistance; factor V deficiency was also observed in these individuals (Lunghi et al. 1998; Segers et al. 2012). The p.Arg740Ter variant was also detected in one of the probands' son (affected status unknown) and in an unrelated individual who had reduced factor V levels (Lunghi et al. 1998). The variant was also found in two unaffected relatives in a heterozygous state (Montefusco et al. 2003). Control data are unavailable for this variant, which is not found in the 1000 Genomes Project, the Exome Sequencing Project, or the Exome Aggregation Consortium. Based on the evidence and the potential impact of stop-gained variants, the p.Arg740Ter variant is classified as likely pathogenic for Factor V deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Uncertain	0.35
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.76	D
MutationTaster	Benign	1.0	A;A
Vest4		0.74
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs757953549; hg19: chr1-169512110; COSMIC: COSV100888970;