1-169542317-T-C

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.2773A>G(p.Lys925Glu) 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 1,613,780 control chromosomes in the GnomAD database, including 60,109 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (4743 hom., cov: 31)
  • Exomes 𝑓: 0.27 (55366 hom.)
• Consequence: F5 NM_000130.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.376

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=0.0026506782).
• BP6: Variant 1-169542317-T-C is Benign according to our data. Variant chr1-169542317-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 255202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-169542317-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	UniProt
F5	NM_000130.5	c.2773A>G	p.Lys925Glu	missense_variant	13/25	ENST00000367797.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F5	ENST00000367797.9	c.2773A>G	p.Lys925Glu	missense_variant	13/25	1	NM_000130.5	P2
F5	ENST00000367796.3	c.2788A>G	p.Lys930Glu	missense_variant	13/25	5		A2

Frequencies

GnomAD3 genomes AF: 0.245 AC: 37254 AN: 151954 Hom.: 4731 Cov.: 31

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: 0.242

Gnomad NFE AF: 0.267

Gnomad OTH AF: 0.261

GnomAD3 exomes AF: 0.279 AC: 69910 AN: 251014 Hom.: 10545 AF XY: 0.278 AC XY: 37764 AN XY: 135630

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: 0.285

GnomAD4 exome AF: 0.272 AC: 397264 AN: 1461708 Hom.: 55366 Cov.: 64 AF XY: 0.273 AC XY: 198289 AN XY: 727160

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: 37295 AN: 152072 Hom.: 4743 Cov.: 31 AF XY: 0.247 AC XY: 18356 AN XY: 74356

Gnomad4 AFR AF: 0.183

Gnomad4 AMR AF: 0.342

Gnomad4 ASJ AF: 0.168

Gnomad4 EAS AF: 0.234

Gnomad4 SAS AF: 0.323

Gnomad4 FIN AF: 0.211

Gnomad4 NFE AF: 0.267

Gnomad4 OTH AF: 0.260

Alfa AF: 0.261 Hom.: 4501

Bravo AF: 0.254

TwinsUK AF: 0.270 AC: 1000

ALSPAC AF: 0.280 AC: 1080

ESP6500AA AF: 0.184 AC: 812

ESP6500EA AF: 0.274 AC: 2355

ExAC AF: 0.274 AC: 33213

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, 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	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

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
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.88	T
BayesDel_noAF	Benign	-0.90
Cadd	Benign	0.062
Dann	Benign	0.24
DEOGEN2	Benign	0.013	T;T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.00071	N
LIST_S2	Benign	0.25	T;T
MetaRNN	Benign	0.0027	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-0.51	N;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.46	T
PROVEAN	Benign	0.42	N;N
REVEL	Benign	0.077
Sift	Benign	1.0	T;T
Sift4G	Benign	0.99	T;T
Polyphen		0.0	B;.
Vest4		0.038
MPC		0.12
ClinPred		0.0040	T
GERP RS		-5.1
Varity_R		0.040
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: rs6032; hg19: chr1-169511555; COSMIC: COSV63120680;