rs6022

chr1-169560588-C-Achr1-169560588-C-Gchr1-169560588-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000130.5(F5):c.552G>T(p.Ser184=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.213 in 1,613,178 control chromosomes in the GnomAD database, including 47,929 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S184S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.32 (10496 hom., cov: 31)
  • Exomes 𝑓: 0.20 (37433 hom.)
• Consequence: F5 NM_000130.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.639

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 1-169560588-C-A is Benign according to our data. Variant chr1-169560588-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 255212.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-169560588-C-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.639 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.634 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
F5	NM_000130.5	c.552G>T	p.Ser184=	synonymous_variant	4/25	ENST00000367797.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F5	ENST00000367797.9	c.552G>T	p.Ser184=	synonymous_variant	4/25	1	NM_000130.5	P2
F5	ENST00000367796.3	c.552G>T	p.Ser184=	synonymous_variant	4/25	5		A2

Frequencies

GnomAD3 genomes AF: 0.322 AC: 48902 AN: 151662 Hom.: 10474 Cov.: 31

Gnomad AFR AF: 0.582

Gnomad AMI AF: 0.0877

Gnomad AMR AF: 0.292

Gnomad ASJ AF: 0.205

Gnomad EAS AF: 0.653

Gnomad SAS AF: 0.194

Gnomad FIN AF: 0.256

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.177

Gnomad OTH AF: 0.300

GnomAD3 exomes AF: 0.261 AC: 65679 AN: 251384 Hom.: 11764 AF XY: 0.248 AC XY: 33668 AN XY: 135854

Gnomad AFR exome AF: 0.589

Gnomad AMR exome AF: 0.269

Gnomad ASJ exome AF: 0.211

Gnomad EAS exome AF: 0.678

Gnomad SAS exome AF: 0.178

Gnomad FIN exome AF: 0.255

Gnomad NFE exome AF: 0.174

Gnomad OTH exome AF: 0.237

GnomAD4 exome AF: 0.202 AC: 294949 AN: 1461400 Hom.: 37433 Cov.: 35 AF XY: 0.199 AC XY: 144917 AN XY: 727034

Gnomad4 AFR exome AF: 0.594

Gnomad4 AMR exome AF: 0.273

Gnomad4 ASJ exome AF: 0.210

Gnomad4 EAS exome AF: 0.600

Gnomad4 SAS exome AF: 0.175

Gnomad4 FIN exome AF: 0.257

Gnomad4 NFE exome AF: 0.170

Gnomad4 OTH exome AF: 0.246

GnomAD4 genome AF: 0.323 AC: 48970 AN: 151778 Hom.: 10496 Cov.: 31 AF XY: 0.325 AC XY: 24076 AN XY: 74184

Gnomad4 AFR AF: 0.582

Gnomad4 AMR AF: 0.292

Gnomad4 ASJ AF: 0.205

Gnomad4 EAS AF: 0.652

Gnomad4 SAS AF: 0.193

Gnomad4 FIN AF: 0.256

Gnomad4 NFE AF: 0.177

Gnomad4 OTH AF: 0.305

Alfa AF: 0.197 Hom.: 5740

Bravo AF: 0.340

Asia WGS AF: 0.450 AC: 1563 AN: 3478

EpiCase AF: 0.173

EpiControl AF: 0.175

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

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. -

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	-0.39
Cadd	Benign	0.096
Dann	Benign	0.40
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: rs6022; hg19: chr1-169529826; COSMIC: COSV63123820;