rs6024

chr1-169542801-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000130.5(F5):c.2289A>G(p.Glu763=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0611 in 1,614,122 control chromosomes in the GnomAD database, including 3,539 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.055 (357 hom., cov: 32)
  • Exomes 𝑓: 0.062 (3182 hom.)
• Consequence: F5 NM_000130.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.153

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 1-169542801-T-C is Benign according to our data. Variant chr1-169542801-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 255195.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-169542801-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.153 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.098 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
F5	NM_000130.5	c.2289A>G	p.Glu763=	synonymous_variant	13/25	ENST00000367797.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F5	ENST00000367797.9	c.2289A>G	p.Glu763=	synonymous_variant	13/25	1	NM_000130.5	P2
F5	ENST00000367796.3	c.2304A>G	p.Glu768=	synonymous_variant	13/25	5		A2

Frequencies

GnomAD3 genomes AF: 0.0549 AC: 8362 AN: 152182 Hom.: 356 Cov.: 32

Gnomad AFR AF: 0.0111

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.102

Gnomad ASJ AF: 0.0752

Gnomad EAS AF: 0.0300

Gnomad SAS AF: 0.0735

Gnomad FIN AF: 0.0836

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0664

Gnomad OTH AF: 0.0670

GnomAD3 exomes AF: 0.0654 AC: 16420 AN: 251174 Hom.: 677 AF XY: 0.0662 AC XY: 8981 AN XY: 135734

Gnomad AFR exome AF: 0.00898

Gnomad AMR exome AF: 0.0957

Gnomad ASJ exome AF: 0.0699

Gnomad EAS exome AF: 0.0303

Gnomad SAS exome AF: 0.0741

Gnomad FIN exome AF: 0.0855

Gnomad NFE exome AF: 0.0628

Gnomad OTH exome AF: 0.0740

GnomAD4 exome AF: 0.0618 AC: 90301 AN: 1461822 Hom.: 3182 Cov.: 48 AF XY: 0.0626 AC XY: 45531 AN XY: 727218

Gnomad4 AFR exome AF: 0.00908

Gnomad4 AMR exome AF: 0.0962

Gnomad4 ASJ exome AF: 0.0705

Gnomad4 EAS exome AF: 0.0599

Gnomad4 SAS exome AF: 0.0738

Gnomad4 FIN exome AF: 0.0835

Gnomad4 NFE exome AF: 0.0597

Gnomad4 OTH exome AF: 0.0619

GnomAD4 genome AF: 0.0549 AC: 8364 AN: 152300 Hom.: 357 Cov.: 32 AF XY: 0.0572 AC XY: 4262 AN XY: 74468

Gnomad4 AFR AF: 0.0110

Gnomad4 AMR AF: 0.102

Gnomad4 ASJ AF: 0.0752

Gnomad4 EAS AF: 0.0301

Gnomad4 SAS AF: 0.0736

Gnomad4 FIN AF: 0.0836

Gnomad4 NFE AF: 0.0664

Gnomad4 OTH AF: 0.0668

Alfa AF: 0.0625 Hom.: 224

Bravo AF: 0.0514

Asia WGS AF: 0.0630 AC: 218 AN: 3478

EpiCase AF: 0.0628

EpiControl AF: 0.0635

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Thrombophilia due to activated protein C resistance Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Congenital factor V deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Budd-Chiari syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Factor V deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 19, 2019

- -

Thrombophilia due to thrombin defect Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	0.52
Dann	Benign	0.46
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: rs6024; hg19: chr1-169512039; COSMIC: COSV63127429;