rs4525

Positions:

• chr1-169542496-T-C
• chr1-169542496-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000130.5(F5):​c.2594A>G​(p.His865Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.269 in 1,613,802 control chromosomes in the GnomAD database, including 60,144 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (4755 hom., cov: 32)
  • Exomes 𝑓: 0.27 (55389 hom.)
• Consequence: F5 NM_000130.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.391

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.5651875E-4).
• BP6: Variant 1-169542496-T-C is Benign according to our data. Variant chr1-169542496-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 255201.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-169542496-T-C is described in Lovd as [Benign].
• 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	Protein	UniProt
F5	NM_000130.5	c.2594A>G	p.His865Arg	missense_variant	13/25	ENST00000367797.9	NP_000121.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F5	ENST00000367797.9	c.2594A>G	p.His865Arg	missense_variant	13/25	1	NM_000130.5	ENSP00000356771	P2
F5	ENST00000367796.3	c.2609A>G	p.His870Arg	missense_variant	13/25	5		ENSP00000356770	A2

Frequencies

GnomAD3 genomes AF: 0.245 AC: 37279 AN: 152026 Hom.: 4745 Cov.: 32

Gnomad AFR AF: 0.183

Gnomad AMI AF: 0.191

Gnomad AMR AF: 0.341

Gnomad ASJ AF: 0.168

Gnomad EAS AF: 0.234

Gnomad SAS AF: 0.323

Gnomad FIN AF: 0.211

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.267

Gnomad OTH AF: 0.261

GnomAD3 exomes AF: 0.278 AC: 69851 AN: 250816 Hom.: 10539 AF XY: 0.278 AC XY: 37723 AN XY: 135520

Gnomad AFR exome AF: 0.179

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: 0.286

GnomAD4 exome AF: 0.272 AC: 397345 AN: 1461662 Hom.: 55389 Cov.: 57 AF XY: 0.273 AC XY: 198318 AN XY: 727126

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: 37316 AN: 152140 Hom.: 4755 Cov.: 32 AF XY: 0.247 AC XY: 18362 AN XY: 74396

Gnomad4 AFR AF: 0.183

Gnomad4 AMR AF: 0.341

Gnomad4 ASJ AF: 0.168

Gnomad4 EAS AF: 0.234

Gnomad4 SAS AF: 0.324

Gnomad4 FIN AF: 0.211

Gnomad4 NFE AF: 0.267

Gnomad4 OTH AF: 0.260

Alfa AF: 0.266 Hom.: 10728

Bravo AF: 0.254

TwinsUK AF: 0.270 AC: 1002

ALSPAC AF: 0.281 AC: 1082

ESP6500AA AF: 0.185 AC: 814

ESP6500EA AF: 0.274 AC: 2356

ExAC AF: 0.274 AC: 33228

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

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

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Labcorp Genetics (formerly Invitae), Labcorp

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
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.84	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.020
DANN	Benign	0.34
DEOGEN2	Benign	0.084	T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.39	T;T
MetaRNN	Benign	0.00086	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.2	M;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.24	T
PROVEAN	Uncertain	-2.5	N;N
REVEL	Benign	0.017
Sift	Benign	0.45	T;T
Sift4G	Benign	0.14	T;T
Polyphen		0.0	B;.
Vest4		0.032
MPC		0.11
ClinPred		0.0047	T
GERP RS		-1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.021
gMVP		0.19

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: rs4525; hg19: chr1-169511734; COSMIC: COSV63120688;