rs6016

Variant names:

• chr1-169542882-G-A
• rs6016
• NM_000130.5:c.2208C>T

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.2208C>T​(p.Ile736Ile) 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 1,613,338 control chromosomes in the GnomAD database, including 60,137 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 (55381 hom.)
• Consequence: F5 NM_000130.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.212

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=-0.71).
• BP6: Variant 1-169542882-G-A is Benign according to our data. Variant chr1-169542882-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 255193.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-169542882-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.212 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 rank	MANE	Protein	UniProt
F5	NM_000130.5	c.2208C>T	p.Ile736Ile	synonymous_variant	Exon 13 of 25	ENST00000367797.9	NP_000121.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F5	ENST00000367797.9	c.2208C>T	p.Ile736Ile	synonymous_variant	Exon 13 of 25	1	NM_000130.5	ENSP00000356771.3
F5	ENST00000367796.3	c.2223C>T	p.Ile741Ile	synonymous_variant	Exon 13 of 25	5		ENSP00000356770.3

Frequencies

GnomAD3 genomes AF: 0.245 AC: 37284 AN: 152002 Hom.: 4744 Cov.: 32

Gnomad AFR AF: 0.183

Gnomad AMI AF: 0.192

Gnomad AMR AF: 0.341

Gnomad ASJ AF: 0.168

Gnomad EAS AF: 0.235

Gnomad SAS AF: 0.323

Gnomad FIN AF: 0.211

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.267

Gnomad OTH AF: 0.262

GnomAD3 exomes AF: 0.278 AC: 69914 AN: 251090 Hom.: 10546 AF XY: 0.278 AC XY: 37765 AN XY: 135700

Gnomad AFR exome AF: 0.178

Gnomad AMR exome AF: 0.415

Gnomad ASJ exome AF: 0.177

Gnomad EAS exome AF: 0.222

Gnomad SAS exome AF: 0.330

Gnomad FIN exome AF: 0.213

Gnomad NFE exome AF: 0.268

Gnomad OTH exome AF: 0.285

GnomAD4 exome AF: 0.272 AC: 397076 AN: 1461218 Hom.: 55381 Cov.: 40 AF XY: 0.273 AC XY: 198201 AN XY: 726928

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: 152120 Hom.: 4756 Cov.: 32 AF XY: 0.247 AC XY: 18365 AN XY: 74364

Gnomad4 AFR AF: 0.183

Gnomad4 AMR AF: 0.342

Gnomad4 ASJ AF: 0.168

Gnomad4 EAS AF: 0.235

Gnomad4 SAS AF: 0.324

Gnomad4 FIN AF: 0.211

Gnomad4 NFE AF: 0.267

Gnomad4 OTH AF: 0.260

Alfa AF: 0.265 Hom.: 10862

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:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Nov 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Thrombophilia due to activated protein C resistance Benign:2

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital factor V deficiency Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Budd-Chiari syndrome Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Thrombophilia due to thrombin defect Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.71
CADD	Benign	1.4
DANN	Benign	0.63

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: rs6016; hg19: chr1-169512120; COSMIC: COSV63120727;