rs6021

chr1-169542789-T-Cchr1-169542789-T-G

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.2301A>G(p.Ser767=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.269 in 1,613,850 control chromosomes in the GnomAD database, including 60,148 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (4756 hom., cov: 32)
  • Exomes 𝑓: 0.27 (55392 hom.)
• Consequence: F5 NM_000130.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.12

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=-0.88).
• BP6: Variant 1-169542789-T-C is Benign according to our data. Variant chr1-169542789-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 255196.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-169542789-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.12 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.334 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
F5	NM_000130.5	c.2301A>G	p.Ser767=	synonymous_variant	13/25	ENST00000367797.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F5	ENST00000367797.9	c.2301A>G	p.Ser767=	synonymous_variant	13/25	1	NM_000130.5	P2
F5	ENST00000367796.3	c.2316A>G	p.Ser772=	synonymous_variant	13/25	5		A2

Frequencies

GnomAD3 genomes AF: 0.245 AC: 37285 AN: 152018 Hom.: 4745 Cov.: 32

Gnomad AFR AF: 0.183

Gnomad AMI AF: 0.191

Gnomad AMR AF: 0.341

Gnomad ASJ AF: 0.169

Gnomad EAS AF: 0.234

Gnomad SAS AF: 0.323

Gnomad FIN AF: 0.210

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.266

Gnomad OTH AF: 0.263

GnomAD3 exomes AF: 0.278 AC: 69942 AN: 251178 Hom.: 10548 AF XY: 0.278 AC XY: 37777 AN XY: 135746

Gnomad AFR exome AF: 0.179

Gnomad AMR exome AF: 0.415

Gnomad ASJ exome AF: 0.177

Gnomad EAS exome AF: 0.221

Gnomad SAS exome AF: 0.330

Gnomad FIN exome AF: 0.213

Gnomad NFE exome AF: 0.268

Gnomad OTH exome AF: 0.286

GnomAD4 exome AF: 0.272 AC: 397369 AN: 1461716 Hom.: 55392 Cov.: 45 AF XY: 0.273 AC XY: 198335 AN XY: 727168

Gnomad4 AFR exome AF: 0.180

Gnomad4 AMR exome AF: 0.409

Gnomad4 ASJ exome AF: 0.176

Gnomad4 EAS exome AF: 0.226

Gnomad4 SAS exome AF: 0.325

Gnomad4 FIN exome AF: 0.217

Gnomad4 NFE exome AF: 0.272

Gnomad4 OTH exome AF: 0.264

GnomAD4 genome AF: 0.245 AC: 37325 AN: 152134 Hom.: 4756 Cov.: 32 AF XY: 0.247 AC XY: 18368 AN XY: 74372

Gnomad4 AFR AF: 0.183

Gnomad4 AMR AF: 0.342

Gnomad4 ASJ AF: 0.169

Gnomad4 EAS AF: 0.235

Gnomad4 SAS AF: 0.324

Gnomad4 FIN AF: 0.210

Gnomad4 NFE AF: 0.267

Gnomad4 OTH AF: 0.260

Alfa AF: 0.254 Hom.: 2178

Bravo AF: 0.254

Asia WGS AF: 0.283 AC: 983 AN: 3478

EpiCase AF: 0.269

EpiControl AF: 0.270

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

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	- -

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

Nov 11, 2018

- -

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	-0.88
Cadd	Benign	0.48
Dann	Benign	0.58
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs6021; hg19: chr1-169512027; COSMIC: COSV63120711;