rs9287090

Variant names:

• chr1-169541142-G-A
• rs9287090
• NM_000130.5:c.3948C>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.3948C>T​(p.Leu1316Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.14 in 1,129,062 control chromosomes in the GnomAD database, including 25,696 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (3178 hom., cov: 26)
  • Exomes 𝑓: 0.13 (22518 hom.)
• Consequence: F5 NM_000130.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -1.57

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=-0.86).
• BP6: Variant 1-169541142-G-A is Benign according to our data. Variant chr1-169541142-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 255206.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-169541142-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.57 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.308 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F5	NM_000130.5	c.3948C>T	p.Leu1316Leu	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.3948C>T	p.Leu1316Leu	synonymous_variant	Exon 13 of 25	1	NM_000130.5	ENSP00000356771.3
F5	ENST00000367796.3	c.3963C>T	p.Leu1321Leu	synonymous_variant	Exon 13 of 25	5		ENSP00000356770.3

Frequencies

GnomAD3 genomes AF: 0.222 AC: 31944 AN: 144082 Hom.: 3173 Cov.: 26

Gnomad AFR AF: 0.164

Gnomad AMI AF: 0.173

Gnomad AMR AF: 0.315

Gnomad ASJ AF: 0.159

Gnomad EAS AF: 0.204

Gnomad SAS AF: 0.286

Gnomad FIN AF: 0.185

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.243

Gnomad OTH AF: 0.236

GnomAD3 exomes AF: 0.208 AC: 42178 AN: 202424 Hom.: 7196 AF XY: 0.209 AC XY: 22775 AN XY: 109128

Gnomad AFR exome AF: 0.132

Gnomad AMR exome AF: 0.305

Gnomad ASJ exome AF: 0.0943

Gnomad EAS exome AF: 0.178

Gnomad SAS exome AF: 0.235

Gnomad FIN exome AF: 0.166

Gnomad NFE exome AF: 0.214

Gnomad OTH exome AF: 0.207

GnomAD4 exome AF: 0.128 AC: 126304 AN: 984884 Hom.: 22518 Cov.: 90 AF XY: 0.138 AC XY: 68725 AN XY: 498712

Gnomad4 AFR exome AF: 0.0794

Gnomad4 AMR exome AF: 0.282

Gnomad4 ASJ exome AF: 0.0987

Gnomad4 EAS exome AF: 0.166

Gnomad4 SAS exome AF: 0.236

Gnomad4 FIN exome AF: 0.176

Gnomad4 NFE exome AF: 0.109

Gnomad4 OTH exome AF: 0.145

GnomAD4 genome AF: 0.222 AC: 31968 AN: 144178 Hom.: 3178 Cov.: 26 AF XY: 0.223 AC XY: 15705 AN XY: 70352

Gnomad4 AFR AF: 0.164

Gnomad4 AMR AF: 0.315

Gnomad4 ASJ AF: 0.159

Gnomad4 EAS AF: 0.204

Gnomad4 SAS AF: 0.286

Gnomad4 FIN AF: 0.185

Gnomad4 NFE AF: 0.243

Gnomad4 OTH AF: 0.235

Alfa AF: 0.249 Hom.: 1628

Asia WGS AF: 0.186 AC: 599 AN: 3224

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

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

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 04, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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	-0.86
CADD	Benign	0.71
DANN	Benign	0.42

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: rs9287090; hg19: chr1-169510380; COSMIC: COSV63120672;